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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.
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.
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.
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.
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.
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.
Points & Pearls Excerpt
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King's College Criteria for
Acetaminophen Overdose and
N-Acetylcysteine (NAC) Dosing
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Points to keep in mind:
Why to Use
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
Vincent Nguyen, MD
Department of Emergency Medicine
Bronx, New York
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.
John O'Grady, MD
Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003;31(1):299-305.
Copyright © MDCalc • Reprinted with permission.
Why to Use
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:
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.
If time of ingestion is known:
If time of ingestion is unknown:
If the patient ingested extended release formulations or co-ingested opioids, anticholinergics, or other medications that slow gut motility:
In cases of chronic acetaminophen ingestion:
Scott Lucyk, MD
Department of Emergency Medicine
University of Calgary, Calgary, Alberta, Canada
Poison and Drug Information Service (PADIS)
Alberta Health Services, Calgary, Alberta, Canada
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.
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.
Barry H. Rumack, MD
Copyright © MDCalc • Reprinted with permission.
Todd Taylor, MD; Matthew Wheatley, MD, FACEP
Arlene S. Chung, MD, MACM; Corinne Horan, DO
April 1, 2018
April 30, 2021
Physician CME Information
Date of Original Release: April 1, 2018. Date of most recent review: March 10, 2018. Termination date: April 1, 2021.
Accreditation: EB Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the ACCME.
Credit Designation: EB Medicine designates this enduring material for a maximum of 4 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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.
Needs Assessment: The need for this educational activity was determined by a survey of medical staff, including the editorial board of this publication; review of morbidity and mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for emergency physicians.
Target Audience: This enduring material is designed for emergency medicine physicians, physician assistants, nurse practitioners, and residents.
Goals: Upon completion of this activity, you should be able to: (1) demonstrate medical decision-making based on the strongest clinical evidence; (2) cost-effectively diagnose and treat the most critical presentations; and (3) describe the most common medicolegal pitfalls for each topic covered.
Discussion of Investigational Information: As part of the journal, faculty may be presenting investigational information about pharmaceutical products that is outside Food and Drug Administration–approved labeling. Information presented as part of this activity is intended solely as continuing medical education and is not intended to promote off-label use of any pharmaceutical product.
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