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?
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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Centers for Disease Control and Prevention National Center for Health Statistics. National Hospital Ambulatory Medical Center Care Survey. 2017; https://www.cdc.gov/nchs/ahcd/. (Government data)
Reisman Y, Gips CH, Lavelle SM, et al. Clinical presentation of (subclinical) jaundice--the Euricterus project in The Netherlands. United Dutch Hospitals and Euricterus Project Management Group. Hepatogastroenterology. 1996;43(11):1190-1195. (Prospective; 700 patients)
Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol. 2007;102(3):558-562. (Retrospective; 732 patients)
Lalani T, Couto CA, Rosen MP, et al. ACR appropriateness criteria jaundice. J Am Coll Radiol. 2013;10(6):402-409. (Consensus statement)
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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.
Most Important References
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
Nachi: This is a huge change of pace from our last two episodes – on inhalational injuries and thermal burns - but definitely an important topic, especially at our liver referral center.
Jeff: Yea, definitely important at a liver center, but let’s not act like jaundice is specific to the large academic centers, as there are approximately 52,000 ED visits a year for patients with jaundice.
Most Important References
5. * Lalani T, Couto CA, Rosen MP, et al. ACR appropriateness criteria jaundice. J Am Coll Radiol. 2013;10(6):402-409. (Consensus statement)
29. * 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)
35. * 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)
51. * 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)
79. * 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)
80. * Wolf SJ, Heard K, Sloan EP, et al. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Ann Emerg Med. 2007;50(3):292-313. (Practice guideline)
89. * Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med. 1996;335(8):569-576. (Review)
101. * Lee WM. Acute liver failure. N Engl J Med. 1993;329(25):1862-1872. (Review)
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The King’s College Criteria (KCC) were developed to determine which patients with fulminant hepatic failure (FHF) should be referred for liver transplant.
The KCC can be applied to all acetaminophen ingestions (acute or chronic) with signs of severe acute liver injury.
There are no worldwide standard criteria for transplantation, but the KCC are the most widely applied.
The KCC indicators predict a poor prognosis, and select the patients most likely to benefit from an immediate liver transplant referral.
The etiology of the acute liver failure is important in determining indicators of poor prognosis (acetaminophen ingestion vs other causes).
Metabolic acidosis alone OR a combination of Grade III or IV hepatic encephalopathy (HE), prothrombin time (PT) > 100 sec, and creatinine level > 3.4 mg/dL predicted 77% of total deaths (O'Grady 1989).
Points to keep in mind:
The KCC are criticized for predicting mortality often when patients are too sick for a transplant.
The use of prolonged N-acetylcysteine therapy, which was not standard when the KCC were created, has significantly lowered the complication rate and need for transplants.
PT values are often not comparable across laboratories, due to the use of different reagents.
Serum lactate (a marker of liver injury) and phosphate (a marker of liver regeneration) have been used as alternative early prognostic indicators or adjuncts to the KCC.
The KCC is specific but not sensitive; that is, while fulfillment of the criteria carries a poor prognosis, lack of fulfillment may still carry an unfavorable outlook.
Acetaminophen poisoning is the most common cause of acute liver failure in the United States, the United Kingdom, and many other countries. The only treatment option that radically improves the outcome of acute liver failure is emergency liver transplantation. Therefore, proper identification of which patients to refer and transfer is critically important. In addition, appropriate transplant candidates must be identified as early as possible to provide a realistic window for a graft to become available.
When to Use
The KCC are used for patients with acetaminophen-induced liver failure, to show the degree of multiorgan dysfunction.
The criteria can be used alone or with serum lactate and phosphate to predict which patients will have a poor prognosis without a liver transplant.
Next Steps
All patients with acetaminophen-induced hepatotoxicity should receive N-acetylcysteine.
Frequent monitoring should be performed for coagulation parameters, complete blood counts, metabolic panels, blood gases, and blood glucose.
Serum aminotransferases and bilirubin should be monitored daily.
Patients should be monitored and treated for hypoglycemia, hypokalemia, and hypophosphatemia.
Administration of fresh frozen plasma is indicated only in the setting of active hemorrhage or prior to invasive procedures in coagulopathic patients. Prophylactic administration of fresh frozen plasma is not recommended, as it does not improve mortality and can interfere with assessments of liver function.
Patients with acute liver failure should be managed in centers with expertise in caring for these patients. This includes patients who do not yet appear to be gravely ill, since it can be hazardous to transfer patients later in the disease course.
The KCC were derived from a retrospective review of 588 patients with FHF over 13 years (O’Grady 1989). The predictors are slightly different based on the etiology of the FHF (acetaminophen vs other causes). The arterial pH, HE, PT, and creatinine predictors were derived from 310 patients with acetaminophen-induced FHF, and were retrospectively validated on a separate group of 121 patients with acetaminophen-induced FHF (O’Grady 1989).
The criteria are well validated and reflect the degree of multiorgan dysfunction. In addition, the criteria are specific but not sensitive; fulfillment of the criteria suggests a poor prognosis, but patients who do not fulfill the criteria may also still have a poor prognosis.
In the study, patients were transferred to King’s College Hospital at a relatively late stage (median time of 51 hours after acetaminophen ingestion) and were the most severely ill (the majority of patients were admitted with HE stages III or IV). This may have affected the predictive values of the test criteria.
In a systematic review of 14 eligible studies (Bailey 2003), the estimated overall sensitivity and specificity of the KCC for predicting mortality were 58% and 95%, respectively. The search for earlier prognostic indicators with a higher sensitivity for poor prognosis led to investigations of alpha-fetoprotein, coagulation factor V, ketone body ratio, lactate, and phosphate. Lactate and phosphate concentrations were initially found to have improved predictive ability compared to the KCC, but subsequent studies have shown slightly inferior predictive ability. The addition of lactate or phosphate to the KCC may improve sensitivity and negative predictive value.
Acetaminophen Overdose and N-Acetylcysteine Dosing calculates oral and intravenous N-acetylcysteine dosing for acetaminophen overdose, and determines the toxic 4-hour level using the Rumack-Matthew nomogram.
An acetaminophen concentration obtained prior to 4 hours post-ingestion cannot be plotted on the Rumack-Matthew nomogram, and only confirms acetaminophen exposure, not toxicity.
It is important to get an accurate time of ingestion, as the Rumack-Matthew nomogram is entirely dependent on knowing time of ingestion.
Start N-acetylcysteine (NAC) treatment within 8 hours post-ingestion to decrease the risk of hepatotoxicity (aspartate transaminase [AST] or alanine transaminase [ALT] > 1000 IU/L).
For patients presenting 8 to 24 hours post-in-gestion, start NAC while awaiting the acetaminophen concentration; NAC can be continued or discontinued depending on the level when the result is available.
NAC is the antidote to acetaminophen toxicity. The Rumack-Matthew nomogram is the most sensitive risk prediction tool in medical toxicology. It identifies patients who are at very low risk of developing hepatotoxicity after an acetaminophen overdose and who do not require NAC. All patients whose plots fall above the treatment line on the nomogram should be treated with NAC to decrease the risk of developing hepatotoxicity.
When to Use
Use the Acetaminophen Overdose and N-Acetylcysteine Dosing tool to calculate for acute, single ingestions of acetaminophen (where entire ingestion occurs within an 8-hour period), with:
A known time of ingestion.
Immediate release formulation.
Absence of formulations or co-ingestants that alter absorption and bowel motility (eg, anticholinergics, opioids).
See the Next Steps section if the time of ingestion is unknown, if an extended release formulation was ingested, or if co-ingestion has occurred.
Next Steps
If time of ingestion is known:
Obtain an acetaminophen concentration at 4 hours post-ingestion or as soon as possible thereafter.
Plot the acetaminophen concentration on the Rumack-Matthew nomogram.
If the plot is above the “treatment line” (the line connecting 150 μg/mL [993 μmol/L] at 4 hours and 4.7 μg/mL [31 μmol/L] at 24 hours), administration of NAC is indicated.
If time of ingestion is unknown:
Determine the earliest possible time of ingestion.
If < 24 hours post-ingestion, plot on Rumack-Matthew nomogram and initiate administration of NAC if plotted above treatment line.
If the earliest time of ingestion cannot be estimated, treatment with NAC is indicated if:
There is a detectable acetaminophen concentration.
There are abnormal aminotransferase (AST or ALT) levels.
If the patient ingested extended release formulations or co-ingested opioids, anticholinergics, or other medications that slow gut motility:
Obtain an initial 4-hour post-ingestion acetaminophen concentration.
If the concentration plots above the Rumack-Matthew nomogram treatment line, treatment with NAC is indicated, and should be initiated within 8 hours post-ingestion.
If the concentration plots above the Rumack-Matthew nomogram treatment line, repeat the acetaminophen concentration testing at 6 to 7 hours post-ingestion.
In cases of chronic acetaminophen ingestion:
For patients taking repeated, supratherapeutic acetaminophen ingestions (> 4 grams per day), treatment with NAC is indicated if:
There is a detectable acetaminophen concentration.
There are abnormal aminotransferase (AST or ALT) levels.
Serum acetaminophen concentration should be obtained for all patients who present with an intentional overdose, or those who have used excessive amounts of acetaminophen-containing products. NAC treatment should be initiated within 8 hours post-ingestion to decrease risk of hepatotoxicity.
Early administration of NAC (< 8 hours post-ingestion) is vital to decreasing the risk of hepatotoxicity; acetaminophen is a leading cause of drug-induced liver injury.
Acetaminophen is widely available in prescription and over-the-counter medications, either as a single agent or in combination products (eg, dextromethorphan, opioids, diphenhydramine).
Maintain a strong index of suspicion for acetaminophen toxicity in all patients with an intentional drug overdose and those with therapeutic misadventures (eg, taking excessive amounts of a single product, or using recommended doses of several different products that contain acetaminophen).
In 1981, Rumack et al published the results of their nationwide, multiclinic open study, which was started in 1976 at the Rocky Mountain Poison Center in Denver. The study was conducted to assess the effectiveness of oral acetylcysteine in preventing hepatotoxicity in patients with acetaminophen overdose presenting within 24 hours of ingestion. The cohort included 662 consecutive patients with an acetaminophen overdose. Incidence of hepa-totoxicity and time to treatment for patients with acetaminophen concentration in the probable toxic range (a line intersecting 200 μg/mL [1324 μmol/L] at 4 hours and 50 μg/mL [331 μmol/L] at 12 hours) were 7% when treated within 10 hours of ingestion, 29% when treated within 10 to 16 hours of ingestion, and 62% when treated within 16 to 24 hours of ingestion.
Prescott et al (1979) studied 100 patients with acetaminophen poisoning who were treated with intravenous NAC. Serum acetaminophen concentrations above a line intersecting 200 μg/mL (1323 μmol/L) at 4 hours and 30 μg/mL (199 μmol/L) at 15 hours were measured, and the incidence of hepatotoxicity was as follows: 0 of 40 patients treated within 8 hours of ingestion, 1 of 62 patients (1.6%) treated within 10 hours of ingestion, and 20 of 38 patients (53%) treated within 10 to 24 hours of ingestion. A retrospective analysis of 57 patients treated with supportive care alone (no intravenous NAC) showed a 58% incidence of hepatotoxicity (33 of 57 patients).
Another study of 11,195 cases of suspected acetaminophen overdose (Smilkstein 1988) described the outcomes of 2540 patients who were treated with 72-hour oral NAC. Among patients at probable risk for hepatotoxicity (acetaminophen concentration above a line intersecting 200 μg/mL [1323 μmol/L] at 4 hours and 50 μg/mL [331 μmol/L] at 12 hours, and below a line intersecting 300 μg/mL [1985 μmol/L] at 4 hours and 75 μg/mL [496 μmol/L] at 12 hours), 6.1% developed hepatotoxicity when NAC was initiated within 10 hours of ingestion, and 26.4% developed hepatotoxicity when NAC was initiated within 10 to 24 hours of ingestion.
4 AMA PRA Category 1 Credits™, 4 ACEP Category I Credits, 4 AAFP Prescribed Credits, 4 AOA Category 2-A or 2-B Credits. Specialty CME Credits: Included as part of the 4 credits, this CME activity is eligible for 0.25 Pharmacology CME credits
Upon competion of this article, you should be able to:
Summarize the pathophysiology of jaundice.
Describe the appropriate emergency department workup for a patient with jaundice.
Describe the life-threatening causes of jaundice.
Discuss the workup and management of neonates and pregnant patients with jaundice.
CME Information
Date of Original Release: April 1, 2018. Date of most recent review: March 10, 2018. Termination date: April 1, 2021.
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ACEP Accreditation: Emergency Medicine Practice is approved by the American College of Emergency Physicians for 48 hours of ACEP Category I credit per annual subscription.
AAFP Accreditation: This Enduring Material activity, Emergency Medicine Practice, has been reviewed and is acceptable for credit by the American Academy of Family Physicians. Term of approval begins 07/01/2017. Term of approval is for one year from this date. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Approved for 4 AAFP Prescribed credits.
AOA Accreditation: Emergency Medicine Practice is eligible for up to 48 American Osteopathic Association Category 2-A or 2-B credit hours per year.
Specialty CME: Included as part of the 4 credits, this CME activity is eligible for 0.25 Pharmacology CME credits, subject to your state and institutional approval.
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