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EBV Hepatitis - 2/27/2013

posted Feb 27, 2013, 8:15 AM by Rohit Das   [ updated Feb 28, 2013, 3:34 PM by Purnema Madahar ]

At resident report yesterday, we talked about a really interesting case of what most likely was EBV hepatitis, in the setting of very high transaminase levels (in the 1000s) and high titers of EBV IgM. She did pretty well…eventually eloped actually…anyway…

·         What are liver transaminases, and why are they used as markers for liver injury?

·         How can liver function test pattern and the degree of transaminase elevation help to narrow your differential?

·         What are the clinical characteristics of EBV-related mononucleosis? How is it diagnosed?

·         Where does EBV hepatitis fall into this framework…?

What are liver transaminases, and why are they used as markers for liver injury?

·         Serum aminotransferases, a.k.a “transaminases,” are sensitive markers of liver injury. Their utility was first described in the literature in 1955. The enzymes we look at are alanine aminotransferase (or ALT, formerly SGPT – serum glutamic pyruvic transaminase) and aspartate aminotransferase (or AST, formerly SGOT - serum glutamic oxaloacetic transaminase).

·         ALT and AST catalyze the transfer of alanine and L-aspartic acid, respectively, to the α-keto group of ketoglutaric acid. I know what you’re thinking – who cares? I then argue – if you’re going to order something as common as LFTs, it’s a good idea to know what the hell you’re exactly ordering.

·         AST is a cytolsolic and mitochondrial enzyme that is found mostly in the liver, but also in several other parts of the body – cardiac muscle, skeletal muscle, kidney, brain…the list goes on. ALT, on the other hand, is purely a cytosolic enzyme and has its highest concentration in the liver, and therefore is a much more specific indicator of liver injury. Additionally, AST is cleared much more rapidly in the serum than ALT, which is important when trying to interpret trends in liver function test pattern. Furthermore, the degree of AST or ALT elevation does NOT correlate with extent of liver injury, but does have etiologic implications...

How can the degree of transaminase elevation help to narrow your differential?

·         Our particular patient, as mentioned, had both AST and ALT levels in the 1000s. Otherwise, both her alkaline phosphatase and bilirubin levels are only mildly elevated. This speaks to a predominantly hepatocellular pattern, and recognizing that certainly limits your differential.

·         More along those lines, there are only a handful processes that cause  transaminase levels to reach the 1000s…

o   Viral Hepatitis – quite a common cause of acute liver failure/injury. The most important etiologies include Hepatitis A, B and C, the latter two being the most common in our epidemiologic world. Some important numbers – 30% of cases acute Hep B exposure will present clinically, and <5% of adults will become chronically infected. On the other hand, only 10% of acute Hep C exposures will present clinically, though 60-80% of patients become chronically infected, and 20-30% of those patients will become cirrhotic over a 20-30 year timeframe…phew.

o   Drug Induced Liver Injury – depending on what epidemiologic study you look at, Tylenol overdose is the most common cause of both severe acute liver injury and acute liver failure. Tylenol, along with drugs like INH, phenytoin, methyldopa, diclofenac, follow predominantly a hepatocellular injury pattern. The second most common cause of DILI, Augmentin, follows more of a cholestatic pattern.

o   Autoimmune Hepatitis – though a rare disease (~2 cases per 100,000 person-years), autoimmune hepatitis can initially present with fulminant disease, and can definitely give you very high transaminase levels. Worth reviewing my daily on this one, but the workup of this consists of serologies, immunoglobulin levels, exclusion of the above, and usually biopsy.

o   Wilson’s Disease – ok…this is really rare (occurs worldwide, about 1 every 50,000 births), but quite unique, and it can also present with fulminant liver failure. One of the unique aspects of Wilson’s is that leads to sub-normal or even low Alk Phos levels – this has do with Zn being a cofactor for Alk Phos synthesis, and unbound Cu antagonizing Zn binding sites…workup involves serum ceruloplasmin levels, looking at the patient’s eyes and urinary copper excretion…

o   Others – some other things that cause transaminase levels to really shoot up – Budd-Chiari syndrome, acute biliary obstruction (early in the course) and ischemic liver injury.

Ok…time to focus…

What are the clinical characteristics of EBV-related mononucleosis? How is it diagnosed?

·         Exposure to EBV is common – in the U.S., serocoversion has occurred in up to 50% of the adult population. In developing countries, where exposure usually occurs much earlier in life, 90-95% of the adult population has seroconverted. Clinically apparent mononucleosis during first exposure to EBV is common – 50 cases per 100,000 person-years, usually in the age range of 15-25, and being much more incident in whites (30-fold) than blacks. In young adults, it’s thought that tongue to tongue action leads to most cases of clinical mononucleosis…

·         EBV incubates for 1-2 months before usually causing days of a prodromal, nonspecific illness followed by the typical symptoms of soar throat (80%) and fevers (80%), accompanied by the specific signs of pharyngitis (85%), cervical lymphadenopathy (95%) and > 50% mononuclear cells with >10% being atypical-looking. Almost pathognomic for EBV-mononucleosis is the development of a pruritic, maculopapular eruption following administration of ampicillin/amoxicillin…one can imagine this being a relatively common scenario when such patients are treated for presumed Streptococcal pharyngitis…EBV-mononucleosis can also have system-specific complications, and EBV itself has malignant implications, but I shan’t dwell on that today at least…

·         The classic test for EBV-mononucleosis is the detection of heterophile antibodies, which by definition, are antibodies that react with different proteins across different species lines. The initial literature, in 1932, described such antibodies against sheep RBCs (the Paul-Bunnell test); the test has since been refined to be against horse RBCs (the “Monospot” test). It’s pretty sensitive (85-90%, but can be lower early in the course), and is 100% specific. Other, more accurate, tests are specific EBV antibodies, particularly IgM against the EBV-virus capsid antigens (VCA IgM – what our lab does). These antibodes are NOT present in the general population, are present in 95% of patients early in the mononucleosis course (and present in all patients later in the course) and fall to undetectable titers 2-3 months after diagnosis. BUT, VCA IgM can be falsely positive in the setting of acute CMV infection (which can cause a heterophile-negative mononucleosis syndrome)…our patient was probably not suspect to that confounder, as testing did not detect CMV IgM.

 

Where does EBV hepatitis fall into this framework…?

·         Have to say, this patient’s diagnosis was incredibly confusing. All testing for viral hepatitis was negative. Though her ANA was positive at a 1:80 titer and homogeneous, her anti-smooth muscle antibody was negative, and her IgG levels were normal. Ceruloplasmin normal. EVERYTHING else normal. So, the only we had going for any etiology was a nonspecific ANA, and a positive EBV IgM, but even that was complicated by TWO negative Monospots and the lack of a characteristic mononucleosis presentation…so, we dived into the literature…

·         Over at a “Jaundice Center” in England, investigators identified around 900 patients with a hepatocellular liver injury pattern over a 13 year timeframe. Of those patients, 17 were diagnosed with EBV-hepatitis with either a positive Monospot and/or positive VCA IgM. Some notable things:

o   Only 2/17 of the patients had transaminase levels above 1000, and only 2/17 presented with the classical features of infectious mononucleosis - fever, pharyngitis and lymphadenopathy.

o   Of the 17 patients, only 1 was heterophile negative but positive for VCA IgM…so that aspect of our patient remains highly atypical…but at least possible!

o   All patients fully recovered, reinforcing that EBV is usually a self-limited illness with good prognosis.

 

So, I’m not really entirely sure what this patient has, but given the data, and the fact that are LFTs trended down pretty fast, the most likely etiology is EBV hepatitis…with Autoimmune disease still being within the realm of possibility. Anyway, I’ve attached the case series I mentioned above, as well as a decent review article…


Epstein-Barr Virus Infectious Mononucleosis
Papesch et. al., Clin. Otolaryngol 2001, Volume 26 (1): 3-8

Vine et. al., Aliment Pharmacol Ther 2012, Volume 36: 16-21
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