Epstein-Barr Virus: Forgotten Etiology of Hepatic Injury - Clinical Advisor
A 20 year-old-man presents to the primary care clinic with abdominal pain, nausea, and vomiting for 7 days as well as right-sided headache, photophobia, phonophobia, and back pain.
The patient reports subjective fever starting 2 days ago along with chills, runny nose, and intermitting blood in the mucous when he blows his nose. He notes mild lightheadedness and says he is dehydrated because he is unable to tolerate liquid or solids. He denies diarrhea or constipation. He tried over-the-counter cold and flu medications containing acetaminophen, dextromethorphan, and phenylephrine with no symptom relief. He denies recent travel or known contacts with anyone who was ill, is not currently taking any daily medications, and has no known drug allergies or history of abdominal surgeries.
Physical Examination
The patient's vital signs are stable. On physical examination, the patient shows tenderness to both light and deep touch at that left-lower quadrant and midepigastric region and complains of midback pain associated with palpation of the midepigastric region. The differential diagnosis includes viral gastritis, gastric ulcer, and acute pancreatitis.
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The patient is discharged home on ondansetron 4 mg and acetaminophen 325 mg. He is sent for laboratory testing and asked to return the next day for re-evaluation. The patient follows up the next day and reports a decreased headache but continued gastroenteric symptoms.
Diagnostic Testing
Initial laboratory results show abnormal findings: elevated levels of alanine aminotransferase (ALT; 1041 U/L) and aspartate aminotransferase (AST; 832 U/L) with a normal lipase level (Table 1). Repeat laboratory testing the following day shows an increase in ALT to 1136 U/L and a decrease in ASL to 812 U/L as well as additional findings of elevated levels of γ-glutamyltransferase (GGT; 482 U/L) and alkaline phosphatase (680 U/L). His acetaminophen level is normal. The calculated R ratio suggests a mixed cholestatic etiology of hepatic injury. [See Discussion section for more on R ratio] The patient is still having difficulty consuming solids or liquids because of continued nausea and vomiting.
Management
The patient is directed to the emergency department (ED) for further evaluation. Computed tomography (CT) without contrast is completed and reported as normal. The patient continues to be unable to tolerate any solids or liquids while in the ED, resulting in hospital admission for acute hepatic injury of unknown etiology. The patient's workup includes tests for drug-induced hepatitis, autoimmune hepatitis, alcohol-related hepatitis, and viral hepatitis that include cytomegalovirus, herpes simplex virus, and Epstein-Barr virus (EBV).
The patient has a positive monospot indicating that EBV is the cause of hepatic injury. He is hospitalized for 5 days, with progression from IV fluids to oral tolerance; his liver enzymes trend downward during the course of hospitalization. On discharge, his ALT is 320 U/L, AST 152 U/L, and alkaline phosphatase 80 U/L. He is monitored by his primary care clinician with weekly blood draws until his liver enzymes normalize 3 weeks after hospital discharge (Table 1).
Table 1. Liver Function Tests Over Time
| Alkaline phoshatase (U/L) | ALT (U/L) | AST (U/L) | Total bilirubin (mg/dL) | |
| Normal | 38-126 | 13-69 | 15-46 | 0.2-1.3 |
| Day 1 | 553 | 1041 | 832 | 4.2 |
| Day 2 | 680 | 1136 | 812 | 4.2 |
| Day 3 | 594 | 838 | 605 | 3.8 |
| Day 4 | 694 | 865 | 657 | 4.0 |
| Day 5 | 791 | 930 | 669 | 4.6 |
| Day 6 | 772 | 835 | 507 | 4.5 |
| Day 8 | 841 | 785 | 420 | 4.3 |
| Day 11 | 543 | 597 | 291 | 2.9 |
| Day 17 | 300 | 264 | 97 | 2.2 |
| Day 24 | 146 | 85 | 43 | 2.2 |
Discussion
Abnormal liver enzymes are commonly seen in the primary care setting.1 These incidental findings require repeat laboratory panels to confirm the abnormality.2 Schreiner et al conducted a 9-year retrospective review of more than 9000 patients in a patient-centered medical home and found that 12% of patients with abnormal liver test results did not receive repeat testing.3 Failure to address and monitor abnormal liver enzymes could lead to deleterious results. If repeat laboratory results concur with the initial findings, further workup should be completed to identify the etiology of hepatic injury.
Acute liver injury is defined as the presence of abnormal liver enzyme tests for less than 6 months in a patient without pre-existing liver disease; chronic liver injury is defined as the presence of abnormal liver enzyme tests for greater than 6 months.4 The term acute liver injury used in clinical settings is synonymous with acute hepatic injury. These terms describe a condition in which the liver has been injured to the point that it produces abnormal liver test findings but has not been damaged. Supportive care is the mainstay of treatment for acute liver injury and patients often recover with minimal to no long-term effects.5
Hepatitis, on the other hand, can be acute or chronic and results from acute liver inflammation or enlargement that causes distention of the liver capsule and may manifest as acute right upper quadrant pain.6 Fulminant hepatitis (liver failure) can be acute or chronic and occurs when the degree of liver injury interferes with liver function resulting in nausea, vomiting, malaise, fluid retention, altered mental status, and jaundice.4 Abdominal trauma also can cause liver damage resulting in hematomas, lacerations, crush injuries, or vascular avulsions.
In the primary care setting, EBV is a well-known cause of sore throat, is the primary cause of infectious mononucleosis, and has a lifetime prevalence of 90% worldwide.5,7,8 In addition to headache, low-grade fever, malaise, and tonsillitis and/or pharyngitis, patients with EBV often experience severe fatigue, nausea, vomiting, and anorexia; mild hepatitis is observed in approximately 90% of those infected.5 The standard treatment for EBV-related mild hepatitis is symptomatic management and continued laboratory monitoring.5
As demonstrated in this case, EBV may present with liver injury characterized by acute cholestatic hepatitis, although this occurs infrequently.5,7 Cases of liver failure with fatal outcomes in patients with EBV infection have been reported, underscoring the importance of laboratory monitoring, particularly in patients with severe EBV symptoms.7
Etiology of Hepatic Injury
Identifying the etiology of possible hepatic injury requires the clinician to interpret the laboratory findings and differentiating between hepatic causes (eg, viral hepatitis), or cholestatic causes (eg, gallstone obstruction).7 A case can become even more complicated if the underlying etiology affects both organ systems, causing a mixed interpretation of findings.
To distinguish between the types of liver injury — autoimmune, cholestatic, hepatocellular, and infiltrative subtypes — it is helpful to use a comprehensive laboratory evaluation that includes measurement of transaminases, fractionated alkaline phosphatase, and bilirubin levels (Table 2).2,9
Table 2. Patterns of Laboratory Abnormalities by Liver Injury Type2,9
| Type | Pattern |
| Autoimmune | Presents with either a hepatocellular pattern if the hepatocytes are involved (autoimmune hepatitis) or cholestatic pattern if the immune mechanism targets the biliary ducts (eg, primary biliary cirrhosis) |
| Cholestatic | Disproportionate elevation in alkaline phosphatase level as compared with AST and ALT levels |
| Hepatocellular | Disproportionate elevation of AST and ALT levels as compared with the alkaline phosphatase level |
| Infiltrative | Disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels |
An elevated alkaline phosphatase level of hepatic origin may be confirmed by elevation of GGT by fractionated alkaline phosphatase panel, according to the American College of Gastroenterology (ACG) guidelines.2 A mixed pattern of injury is defined as elevation of both alkaline phosphatase and AST/ALT levels. Bilirubin levels also may be elevated in hepatocellular, cholestatic, and mixed patterns of injury.2
The ACG also recommends calculating the R ratio to assess whether the pattern of liver injury is hepatocellular, cholestatic, or mixed.2 The R ratio is calculated by the formula R = (ALT value ÷ ALT ULN) ÷ (alkaline phosphatase value ÷ alkaline phosphatase ULN). Scores of greater than 5 are defined as hepatocellular, less than 2 as cholestatic, and 2 to 5 as a mixed pattern.2
Diagnostic Workup
The ACG recommends testing for viral hepatitis, alcoholic fatty liver disease, autoimmune liver diseases, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, and possible drug-induced liver disease in patients with moderate or greater elevations of ALT and/or AST.2 The most common hepatotropic pathogens of acute hepatitis worldwide are types A, B, C, D, and E.2,10 Viral hepatitis from nonhepatotropic viruses is most often caused by cytomegalovirus, herpes simplex virus, and EBV.2
A detailed investigation should also include the patient's lifestyle, travel history, eating habits, history of prescribed and over-the-counter medicines, use of herbal agents or supplements, genetic dispositions, advanced imaging, and possible biopsy after consulting with a liver specialist.2
Abdominal ultrasound is the clinical image of choice to visualize the liver and gallbladder.2,6 A CT scan can be used to identify hepatomegaly and magnetic resonance imaging (MRI) is often used to exclude other possible causes of abnormal liver function tests.2,6 Differentiating between hepatic injury, hepatitis, and liver failure is complex as the initial abnormal liver enzyme findings could be identical. When consulting an internal medicine specialist, understanding the different terms and various etiologies of hepatic injury could be essential for the patient's best care.
Conclusion
Epstein-Barr virus-associated liver injury is a diagnosis that can be made at the primary care level with guidance/consults from an internal medicine or gastroenterology specialist. Primary care providers must be cognizant of the interpretation of abnormal liver enzymes; know the difference between hepatic injury, hepatitis, and hepatic failure; understand the significance of the R ratio; and remember to consider EBV in the workup for acute abnormal liver enzymes.
Leticia Banker, MPAS, PA-C, is a primary care PA for the US Navy and is stationed in San Diego, CA, and is department head of the Navy Medicine Readiness and Training Command San Diego Miramar; Paige E. Bowman, MD, is a family medicine physician at Naval Hospital Twentynine Palms in San Diego, CA.
References
1. Melendez-Rosado J, Alsaad A, Stancampiano FF, Palmer WC. Abnormal liver enzymes. Gastroenterol Nurs. 2018;41(6):497-507. doi:10.1097/SGA.0000000000000346
2. Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112(1):18-35. doi:10.1038/ajg.2016.517
3. Schreiner AD, Moran WP, Zhang J, et al. Evaluation of liver test abnormalities in a patient-centered medical home: do liver test patterns matter? J Investig Med. 2018;66(8):1118-1123. doi:10.1136/jim-2018-000788
4. Kwo PY. Clinical features of liver disease. In: Saxena R. Practical Hepatic Pathology: A Diagnostic Approach. 2nd ed. Elsevier: 2018:33-42.
5. Shah J, Lingiah V, Pyrsopoulos N, Galan M. Acute liver injury due to severe Epstein-Barr virus infection. ACG Case Rep J. 2020;7(2):e00325. Published 2020 Feb 24. doi:10.14309/crj.0000000000000325
6. Joshi G, Crawford KA, Hanna TN, Herr KD, Dahiya N, Menias CO. US of right upper quadrant pain in the emergency department: diagnosing beyond gallbladder and biliary disease. Radiographics. 2018;38(3):766-793. doi:10.1148/rg.2018170149
7. Fugl A, Andersen CL. Epstein-Barr virus and its association with disease – a review of relevance to general practice. BMC Fam Pract. 2019;20(1):62. doi:10.1186/s12875-019-0954-3
8. Ruppert SD, Fay VP. Pharyngitis: soothing the sore throat. Nurse Pract. 2015;40(7):18-25. doi:10.1097/01.NPR.0000466498.57296.60
9. Musana KA, Yale SH, Abdulkarim AS. Tests of liver injury. Clin Med Res. 2004;2(2):129-131. doi:10.3121/cmr.2.2.129
10. Khuroo MS. A review of acute viral hepatitides including hepatitis E. In: Ozaras R., Arends J, eds. Viral Hepatitis: Acute Hepatitis. Springer; 2019.
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