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Q1: What is the main differential diagnosis of this patient’s initial syndrome?
In this young girl a syndrome of fever, lymphadenopathy, and hepatosplenomegaly were accompanied by intrahepatic cholestasis with high bilirubin and acute hepatocellular damage.
The differential diagnosis initially includes any cause of acute hepatitis (box 1) and/or cholestasis (box 2). The patient was not pregnant, she was not alcoholic, took no medication, and had no history of chronic disease. Serological testing excluded acute viral hepatitis A, B, and C, which may be associated with icterus, low grade fever, lymphadenopathy, and hepatosplenomegaly. Autoimmune hepatitis may present with the same signs and symptoms, although acute icteric hepatitis as a presenting symptom is rather unusual. An important step during differential diagnosis is to exclude Wilson’s disease, which may be present in young adolescents, but acute hepatitis with cholestasis is also unusual. Moreover clinical and laboratory testing failed to diagnose Wilson’s disease in our patient.
Box 1: Differential diagnosis of acute hepatocellular damage
Viral hepatitis (hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus, cytomegalovirus).
Drug reaction (isoniazid, antibiotics, methyldopa)
Ischaemia (hypertension, vascular occlusion).
Metabolic/inherited disorders (Wilson’s disease).
Pregnancy related disorders (acute fatty liver of pregnancy).
Box 2: Acute hepatocellular damage with prominent cholestasis
Icteric viral hepatitis (hepatitis A, hepatitis B, Epstein-Barr virus, cytomegalovirus).
Drug reaction (anabolic steroids, oestrogen).
Granulomatous diseases (mycobacterial infections, sarcoidosis, brucellosis).
Infiltrative malignancies (lymphoma).
Inflammation of intrahepatic bile ducts (acute cholangitis, graft versus host disease, AIDS, cholangiopathy).
Systemic bacterial infection.
Alcoholic liver disease.
Taking into consideration the patient’s age and the acute presentation of her disease (fever, lymphadenopathy, and atypical lymphocytes on blood smear), mononucleosis-like syndrome must also be considered in the list of differential diagnoses (box 3). On the other hand, pharyngitis was not present, the heterophil antibody test was negative, and cholestasis with high bilirubin is very unusual in classical infectious mononucleosis.
Box 3: Differential diagnosis of mononucleosis-like syndrome
Epstein-Barr virus infection.
Toxoplasma gondii infection.
Streptococcal or gonococcal pharyngitis.
Hepatitis virus A or B infection.
Acute HIV infection.
Hodgkin’s or non-Hodgkin’s lymphoma.
Q2: What is the laboratory test of choice you would perform on the third hospital day?
The patient presented with cholestatic jaundice but on the third postadmission day her jaundice suddenly became deeper with a greater increase in unconjugated bilirubin. Moreover an important fall in her haemoglobin level was seen. Therefore, an episode of acute haemolysis complicated the initial clinical presentation in this patient. The direct Coombs test was negative. A spot urine test was positive for haemoglobin and the haptoglobin level was low. The laboratory test of choice was to determine the cold agglutinin titre which was raised (1/1024) with an anti“i” specificity.
The glucose-6-phosphate dehydrogenase level was within normal limits and haemoglobin electrophoresis showed no abnormalities.
Q3: What is the diagnosis and the treatment of this syndrome?
Acute haemolysis due to cold agglutinins together with mononucleosis-like syndrome and icteric hepatitis suggests an acute and severe Epstein-Barr virus infection. The IgM antibodies against Epstein-Barr virus capsid antigen were raised in a titre of 1/320 and the IgG antibodies 1/160. Whole blood examination with polymerase chain reaction for Epstein-Barr virus DNA was positive.
In patients with Epstein-Barr virus hepatitis and/or cholestasis, conservative measures are usually sufficient. In patients in whom haemolysis due to cold agglutinins occur, corticosteroid therapy is controversial but sometimes recommended,1 although it is of proven benefit in the case of autoimmune haemolysis due to warm antibodies.
The patient started folate administration and a short course of corticosteroid treatment. Her condition progressively improved. Packed cell volume, bilirubin, and cold agglutinin titres during follow up are shown in fig 1. She was discharged on the 20th postadmission day with a packed cell volume of 32%, haemoglobin 106 g/l, reticulocyte count 3.9%, total bilirubin 3.8 mg/dl (65 μmol/l), direct bilirubin 3.04 mg/dl (52 μmol/l), and still moderately raised liver enzymes. Six months later the patient was in good health with complete clinical and biochemical recovery.
This young patient presented with a severe Epstein-Barr virus infection complicated by icteric hepatitis and secondary haemolysis due to cold haemagglutinins. Nevertheless, lack of the classical symptoms of infectious mononucleosis and the negative test for heterophil antibodies made the initial diagnosis difficult. The rapid heterophil antibody test has an important role in the diagnose of Epstein-Barr virus infection. However, false negative tests have been reported in 20% of the cases in children and 15% in adults.2
At presentation, a moderate hepatocellular injury, with raised liver enzymes, a normal prothrombin time but unusual high conjugated bilirubin level was predominant. Any other causes of acute hepatocellular damage and intrahepatic cholestasis have been excluded. Acute hepatitis at presentation is reported in 20%–50% of the cases of Epstein-Barr virus infection,3 however, mild hyperbilirubinaemia is present in only half of these patients.4 Cases of cholestasis with clinical relevant deep jaundice are rarely reported,2,5 with peak serum bilirubin levels ranging from 18 mg/dl (308 μmol/l)6 to 23 mg/dl (393 μmol/l).7
During hospitalisation our patient presented a rapid fall in haemoglobin level (from 116 g/l to 63 g/l) and her jaundice became “deeper”. The initial high bilirubin levels resembling predominantly conjugated bilirubin (68% of the total bilirubin level) become more raised with a switch to predominantly unconjugated bilirubin (62.5% of the total bilirubin level).
The finding of high anti-“i” cold agglutinins titre demonstrated that acute haemolysis had complicated the course of the disease. Anti-“i” cold agglutinins may be present in fewer than 2% of patients with Epstein-Barr virus infection8 but clinically relevant haemolytic anaemia is usually mild and self limiting. Severe haemolysis with an important fall in haemoglobin level and deep jaundice, as in our patient, has rarely been described.3 In a previous study, seven patients with primary Epstein-Barr virus infection had peak bilirubin levels of 10.2–23 mg/dl (174–393 μmol/l).7 In five of these seven cases, however, there was evidence for both hepatocellular dysfunction and an ongoing haemolytic process either due to anti-“i” cold agglutinins or due to positive antierythrocyte antibodies.
Deep jaundice with signs of haemolysis always raises the possibility of Wilson’s disease. In our patient serum ceruloplasmin and copper were normal and no increased urinary copper or the presence of Kayser-Fleischer ring could be documented. Although these findings do not absolutely exclude Wilson’s disease, the fact that the patient is healthy now, more than six months after the episode of jaundice, clearly demonstrates that she can not have any chronic metabolic disease.
In conclusion, classical Epstein-Barr virus infection is usually a benign and self limiting disease. Despite this fact, close follow up of cases in order to prevent and identify possible complications is necessary. The present case should raise clinicians’ indices of suspicion for the described unusual complications of the well known syndrome of infectious mononucleosis. A cholestatic form of Epstein-Barr virus induced hepatitis may be present in several cases, while a deepening jaundice may be the result of haemolysis due to cold haemagglutinins.
Epstein-Barr virus infection.
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