18-Year-Old Woman With Fever, Abdominal Pain, and Elevated Liver Enzymes

An 18-year-old woman from rural Minnesota was admitted to the hospital after presenting to a local emergency department with a 3-day history of severe right upper quadrant abdominal pain and a 2-week history of headaches, fever, nausea, and vomiting. A review of systems was otherwise unrevealing. Her only medication was trimethoprim-sulfamethoxazole for a recent urinary tract infection. She had no other notable medical history. She reported rare alcohol use 3 years previously and no recent use of over-the-counter medications or dietary supplements, smoking, illegal drug use, or sexual activity. Physical examination findings and vital signs were unremarkable aside from a temperature of 39.0°C and right upper quadrant tenderness without rebound or guarding. There was no hepatosplenomegaly or flank dullness.

Laboratory studies revealed the following (reference ranges shown parenthetically): alkaline phosphatase, 738 U/L (52-144 U/L); aspartate aminotransferase (AST), 285 U/L (8-43 U/L); alanine aminotransferase (ALT), 417 U/L (7-45 U/L); total bilirubin, 2.3 mg/dL (0.1-1.0 mg/dL); direct bilirubin, 1.2 mg/dL (0.0-0.3 mg/dL); and platelet count, 101 × 10⁹/L (150-450 × 10⁹/L). Her hemoglobin level, leukocyte count, urinalysis results, and amylase, lipase, lactate, electrolyte, and serum creatinine levels were all within normal limits. Results of serologies for acute hepatitis A, B, and C, a heterophile antibody test, and a pregnancy test were negative, and salicylate and acetaminophen levels were unremarkable.

• 1
  Which one of the following possible diagnoses should be confirmed or ruled out immediately?

  • a
    Acute cholangitis
  • b
    Budd-Chiari syndrome
  • c
    Ischemic hepatitis
  • d
    Medication-induced hepatitis
  • e
    West Nile virus infection

The patient's laboratory studies suggest hepatocellular injury with mild hyperbilirubinemia, which can be seen with acute cholangitis caused by choledocholithiasis. Acute cholangitis must be considered in every patient with right upper quadrant pain, fever, and hyperbilirubinemia because it has a high mortality rate if diagnosis is delayed. Initial testing would include liver ultrasonography and blood cultures. Acute Budd-Chiari syndrome can present as right upper quadrant pain with biochemical evidence of hepatocellular injury and occurs when an obstruction in the hepatic veins causes hepatic congestion. However, hepatomegaly and new-onset ascites are usually present and fever would be unusual. Although the differential diagnosis should include Budd-Chiari syndrome, it is associated with lower morbidity and mortality than acute cholangitis. Ischemic hepatitis commonly presents with transaminase elevations greater than 1000 U/L, and a precipitating event such as transient hypotension is usually evident from the history. The course of ischemic hepatitis is often characterized by rapid spontaneous resolution. Medications such as trimethoprim-sulfamethoxazole have uncommonly been associated with acute hepatitis, and this would be a diagnosis of exclusion. West Nile virus infection can also rarely present as acute hepatitis and headache, but severe disease is usually associated with neurologic manifestations, and treatment would be supportive.

The patient underwent abdominal ultrasonography, which revealed a normal-appearing liver and gallbladder with no intrahepatic or extrahepatic duct dilatation. Her spleen was enlarged at 16.7 cm in the craniocaudal position (upper limit of the normal range, 12-13 cm). Doppler ultrasonography showed normal hepatic and portal veins. Computed tomography of the abdomen with intravenous contrast was unrevealing aside from mild splenomegaly with no evidence of portal or hepatic vein thrombosis. At this point, the patient has fever, abdominal pain, elevated transaminase and bilirubin levels, splenomegaly, and thrombocytopenia of unclear etiology.

• 2
  Which one of the following is the least likely cause of this patient's abnormal liver enzyme levels?

  • a
    Autoimmune hepatitis
  • b
    Acute infectious mononucleosis
  • c
    Human granulocytic anaplasmosis
  • d
    Acute alcoholic hepatitis
  • e
    Acute human immunodeficiency virus (HIV) infection

Autoimmune hepatitis is usually a chronic condition but can present as acute hepatitis. Overlap syndromes encompassing autoimmune hepatitis and either primary biliary cirrhosis or primary sclerosing cholangitis can lead to concomitant hyperbilirubinemia. Negative results on a heterophile antibody test do not rule out mononucleosis, and this and other causes of viral hepatitis must remain in the differential diagnosis. Anaplasmosis is caused by a rickettsial-like organism transmitted via the Ixodes scapularis tick. It classically presents with elevated transaminase levels, leukopenia, and thrombocytopenia. Acute alcoholic hepatitis typically presents with an AST:ALT ratio greater than 2, a normal or minimally elevated ALT level, and leukocytosis. Liver enzyme (including alkaline phosphatase) elevations greater than 300 U/L, and certainly greater than 500 U/L, suggest another mechanism of hepatocellular injury. Thus, acute alcoholic hepatitis is unlikely to be the sole cause of hepatitis in this patient. Acute HIV infection can rarely present with the acute hepatitis and constitutional symptoms seen in our patient and is an important diagnosis to consider in an unexplained febrile illness.

The patient's fever and abdominal pain persisted without a unifying diagnosis. The AST and ALT levels increased to 297 U/L and 447 U/L, respectively. Evaluation for autoimmune hepatitis was positive for anti–smooth muscle antibodies (1:20 titer) and antinuclear antibodies (1.3 U; weakly positive, 1.1-2.9 U) and negative for anti–kidney/liver microsome antibodies and antimitochondrial antibodies. Serum evaluations were negative for Anaplasma, Ehrlichia, Bartonella, Babesia, Toxoplasma, HIV (enzyme immunoassay serology), West Nile virus, Q fever, and cytomegalovirus (CMV) IgG and IgM. Ceruloplasmin, C-reactive protein, albumin, and ferritin levels were normal, as were erythrocyte sedimentation rate, prothrombin time, and results from serum protein electrophoresis and blood cultures. A peripheral blood smear showed atypical lymphocytes. Lactate dehydrogenase was elevated at 1247 U/L (122-222 U/L).

• 3
  Which one of the following is the most appropriate next step in management?

  • a
    Corticosteroid treatment for autoimmune hepatitis
  • b
    Confirmatory testing for acute viral hepatitis
  • c
    Liver biopsy
  • d
    Endoscopic retrograde cholangiopancreatography
  • e
    Urine drug screen

Autoimmune hepatitis is a clinical diagnosis based primarily on 4 features: absence of viral markers, presence and level of autoantibodies, elevated serum IgG level, and histologic features on liver biopsy. Our patient's mildly elevated antinuclear antibodies and anti–smooth muscle antibodies do not fit the classic diagnostic criteria for autoimmune hepatitis, and empiric treatment should not be initiated without a firm diagnosis. Serum evaluation to rule out viral hepatitis should be performed before considering a liver biopsy. If evaluation for viral hepatitis yields negative results, a liver biopsy would be the next best step and could help to establish a diagnosis of autoimmune hepatitis. Endoscopic retrograde cholangiopancreatography is indicated when pancreaticobiliary disease is suspected and is not indicated in the evaluation of acute hepatitis. Certain drugs of abuse such as phencyclidine (“angel dust”), cocaine, and 3,4-methylenedioxymethamphetamine (“ecstasy”) may cause hepatotoxicity. A urine drug screen may detect such substances, but the patient reported no exposures.

An HIV viral load was undetectable, ruling out acute HIV infection. Results of repeated testing for CMV IgG and IgM were negative, thus making CMV hepatitis unlikely. Despite negative results on the heterophile antibody test, we suspected that the young woman's symptom complex could be caused by Epstein-Barr virus (EBV) infection. Additional testing was performed.

• 4
  Which one of the following would provide the best evidence to confirm this suspected diagnosis?

  • a
    Atypical lymphocytes on peripheral smear
  • b
    Repeated heterophile antibody test
  • c
    IgM antibodies to EBV viral capsid
  • d
    IgG antibodies to EBV viral capsid and EBV nuclear antigen
  • e
    EBV DNA polymerase chain reaction

Although atypical lymphocytes are detected on peripheral smear in up to 75% of patients with EBV mononucleosis, they have a low specificity for diagnostic purposes. A heterophile IgM antibody test is the initial diagnostic test of choice, but results may be falsely negative within the first 3 weeks after onset of symptoms. If heterophile IgM antibodies are present, no further testing is indicated. If heterophile IgM antibodies are absent and EBV infection is suspected, EBV-specific antibody testing is indicated. In patients with mononucleosis, EBV viral capsid IgM is present at symptom onset, and this finding has a high sensitivity and specificity to confirm or rule out acute infection. Once a patient is infected with EBV, viral capsid IgG antibodies and nuclear antigen IgG antibodies are present for life and can represent either current or previous infection. Epstein-Barr virus DNA quantification via polymerase chain reaction is rarely done in immunocompetent hosts and can yield false-negative results in up to 25% of patients with an acute infection.¹ On rare occasions, test results for EBV viral capsid IgM can be falsely positive. If this is the case, a positive EBV viral capsid IgG result 6 weeks after diagnosis may provide further confirmation if needed.

Our patient's test results were positive for EBV viral capsid IgM, negative for EBV viral capsid IgG, and negative for EBV nuclear antigen IgG, consistent with a diagnosis of acute EBV infection.

• 5
  Which one of the following is the best management strategy for this patient's illness?

  • a
    Intravenous acyclovir if liver enzyme levels continue to increase
  • b
    Prednisone
  • c
    Supportive care
  • d
    No contact sports for the next 7 days
  • e
    Low-protein diet for 6 weeks

Intravenous acyclovir has been shown to reduce oropharyngeal viral shedding during treatment of acute EBV infection but has not been shown to affect peripheral viremia or the duration or severity of symptoms.² No clinical benefit has been identified for the use of corticosteroids in acute EBV infection except in cases of specific complications such as acute upper airway obstruction.³ Treatment for EBV infection is supportive and includes symptomatic relief for fever, pharyngitis, and abdominal pain. Although splenomegaly is common, splenic rupture is a rare complication and most commonly occurs within 3 weeks of symptom onset. Therefore, return to contact sports can be considered after a minimum of 3 weeks. Low-protein diets are often used for patients with severe liver disease to reduce nitrogen metabolite and ammonia levels. Our patient does not have liver failure and can follow a normal diet.

The patient received supportive care and was dismissed from the hospital. On a follow-up visit 1 week later, her symptoms had resolved except for fatigue, and her AST and ALT levels had improved to 123 U/L and 267 U/L, respectively. Her thrombocytopenia and hyperbilirubinemia had also completely resolved.

Discussion

Epstein-Barr virus most commonly presents as the clinical syndrome of infectious mononucleosis, although the virus has been linked to a number of other disorders such as nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin disease, oral hairy leukoplakia, and lymphoproliferative disorders in patients with immunodeficiency. A member of the herpesvirus family, EBV infection is spread by contact with oral secretions, and symptoms become apparent after an incubation period of 30 to 50 days.⁴ Although as many as 90% to 95% of all adults are seropositive and shed the virus in saliva, EBV infection accounts for less than 2% of all cases of adults presenting with pharyngitis.⁵

In children, mononucleosis often causes nonspecific symptoms or no symptoms at all. In adolescents and adults, mononucleosis classically presents (in more than 50% of cases) with the triad of fever, pharyngitis, and cervical, axillary, or inguinal lymphadenopathy.⁴ Fatigue, palatal petechiae, and abdominal pain are also common.¹ Lymphocytosis (≥50% lymphocytes) and 10% or more atypical lymphocytes on peripheral blood smear are present in more than two-thirds of patients and can aid in diagnosis.⁶ On ultrasonography, splenomegaly is present in up to 100% of patients, although it is rarely detected on physical examination.⁵ Splenic rupture occurs in 0.1% of mononucleosis cases, almost never occurs later than 3 weeks after symptom onset, and has been found to be atraumatic in one-half of cases.⁷ Additional less common findings include hematologic abnormalities (mild thrombocytopenia, hemolytic anemia, and disseminated intravascular coagulation), genital ulcers, myocarditis, and acute interstitial nephritis. Upper airway obstruction secondary to mucosal edema and pharyngeal lymphoid hyperplasia may occur in 1% of patients. Neurologic complications including Guillain-Barré syndrome, aseptic meningitis, encephalitis, and cranial nerve palsies are seen in 1% to 5% of patients.^4,5

Elevated liver enzymes occur in 80% to 90% of patients with EBV infections, commonly peak 2 to 3 weeks after symptom onset, and normalize within 3 to 6 weeks after symptom onset. The AST and ALT levels typically do not increase to greater than 5 times the upper limit of normal, although elevations higher than 10 times normal and acute liver failure requiring liver transplant have been reported.⁸ Elevations in alkaline phosphatase and conjugated and unconjugated bilirubin concentrations may also be present.⁹

The diagnosis of mononucleosis is based on compatible clinical findings, the presence of lymphocytosis or atypical lymphocytes, and a positive serologic test result. Heterophile IgM antibodies are measurable in approximately 75% of patients in the first week of illness and 95% in the third week after symptom onset,⁵ with a sensitivity of 85% and a specificity of nearly 100%.¹⁰ If the heterophile antibody test result is negative and there is a high clinical suspicion for mononucleosis, the next best test to order is determination of EBV-specific antibodies. Epstein-Barr viral capsid IgM antibodies are diagnostic for acute infection (97% sensitivity, 94% specificity).¹¹ They are detectable at symptom onset (due to a 30- to 50-day incubation period) and disappear in approximately 3 months. Epstein-Barr viral capsid IgG antibodies appear shortly after symptom onset and are present for life, indicative of current or prior infection. Epstein-Barr virus nuclear antigen IgG antibodies become detectable 6 to 12 weeks after symptom onset and also persist throughout life.

Treatment is supportive, including rest, adequate hydration, and acetaminophen or nonsteroidal anti-inflammatory drugs for fever, throat pain, and abdominal pain. Because of a small risk for splenic rupture, patients should abstain from contact sports for a minimum of 3 to 4 weeks after symptom onset and until the patient is asymptomatic.^5,12 The use of corticosteroids or antiviral therapy remains controversial and the subject of ongoing investigation. A meta-analysis published in 1999 evaluated 5 randomized controlled trials comparing acyclovir and placebo in the treatment of mild to severe disease and found no clinical benefit with acyclovir.² A 2006 Cochrane review concluded that there was insufficient evidence to recommend corticosteroid treatment for uncomplicated infectious mononucleosis.³

The diagnosis of EBV infectious mononucleosis should be considered in young patients with elevated transaminase levels, hyperbilirubinemia, splenomegaly, fever, and abdominal pain, even when the classic findings of pharyngitis and palpable lymphadenopathy are not present. The disorder is diagnosed by detection of either heterophile IgM antibodies or EBV viral capsid IgM antibodies. Treatment is supportive, and the prognosis is excellent.