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Case of the Month

February 2017

A 68-year-old man presented with a 2-day history of fever, chills, myalgia and diarrhoea. He had recently returned from the Hluhluwe Game Park five days previously. He had not taken malaria prophylaxis, and there was no history of significant alcohol or recreational drug use, insect bites or contact with animals or animal products. Accommodation was at the luxury lodge in the game park.

A temperature of 39.2oC was the only clinical finding. His white cell count was 3 x 109/L, platelets 101 x 109/L, INR of 4.8, and elevated AST 570 IU/L and ALT 512 IU/L. A clinical diagnosis of acute hepatitis was made.

Question 1. What is your aetiological differential diagnosis?

Answer to Q1

The following causes of acute hepatitis are associated with significantly elevated transaminases:
  • Acute viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus; Epstein-Barr virus; cytomegalovirus [CMV]); or an acute exacerbation of chronic viral hepatitis (hepatitis B); filoviruses, arenaviruses, Congo-Crimean haemorrhagic fever, Rift Valley fever virus
  • Alcoholic hepatitis
  • TB
  • Medicines: antiretroviral treatment, acetaminophen (paracetamol) toxicity, idiosyncratic drug reactions
  • Autoimmune hepatitis
  • Wilson’s disease
  • Ischaemic hepatitis
  • Sinusoidal obstruction syndrome (veno-occlusive disease)
  • HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and occasionally acute fatty liver of pregnancy
  • Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma, melanoma, or myeloma)
Question 2: Which investigations would you request?
Answer to Q2
  • Acetaminophen level
  • Toxicology screen
  • IgM anti-hepatitis A virus; Hepatitis B surface antigen (HBsAg) and IgM anti-hepatitis B core antigen (anti-HBc); Anti-hepatitis C virus antibody (HCV), hepatitis C viral RNA
  • Based on patient history and risk factors, consider anti-herpes simplex virus antibodies, anti-varicella zoster antibodies, anti-CMV antibodies, CMV antigen, and heterophile antibodies for Epstein-Barr virus
  • Consider tests for special viral pathogens if the patient has had a relevant travel history or contact with ticks or animals
  • Pregnancy test
  • Autoimmune markers (antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal antibodies type 1, immunoglobulin levels)
Hepatitis A, B, C, EBV, CMV, malaria, Coxsackie and tick bite fever serologies were all negative. In addition, stool cultures were negative.

The patient was commenced on IV ciprofloxacin at 400 mg bd. He subsequently showed clinical deterioration. Repeat testing of liver enzymes showed a marked increase in transaminases: AST from 570 to 16826 IU/L and ALT from 512 to 8575 IU/L in four days. At this point, a repeat hepatitis screen as well as a serum BD glucan assay and anti-nuclear factor tested negative. His white cell count dropped to 2.3, platelets to 20 and the INR rose to >16. Procalcitonin performed three days after admission was 1.8 and dropped to 0.3 the following day. There was no resolution of the pyrexia. He developed respiratory failure requiring ventilation. The herpes serology performed on D4 of admission showed a negative HSV 1 and 2 IgG and a positive IgM (HSV 1 and 2 combined). Unfortunately the patient demised the following day. Herpes PCR performed on a stored sample showed a significantly high herpes simplex 2 viral load. Post-mortem liver biopsy revealed viral inclusions with herpes. We present a case with an unusual but fatal cause of hepatitis caused by herpes simplex virus.

Question 3 What is the clinical presentation and the risk factors associated with herpes hepatitis?
Answer to Q3

Herpes simplex virus (HSV) hepatitis is an uncommon complication of HSV infection which was first described in 1969. HSV-1 infection affects the oral mucosa, while HSV-2 is most commonly associated with genital lesions. Patients with HSV hepatitis initially present with nonspecific flu-like symptoms including fever, myalgia, and abdominal pain. Only 30%–50% show characteristic herpetic skin lesions. Although both viruses can cause fulminant hepatic failure, HSV-2 seems to be a more frequent cause, particularly among pregnant women accounting for 63% of the reported cases. The diagnosis is often delayed due to the lack of specific signs or symptoms. Primary and/or recurrent HSV infection can result in disseminated infection leading to fulminant hepatic failure. Although immunocompetent patients can be affected, immunosuppressed patients and pregnant women constitute almost 75% of cases reported thus far with HSV hepatitis. Other patients at risk include those with solid organ or hematopoietic transplantation. More than 50% of patients with HSV hepatitis are only diagnosed at autopsy.

Question 4 How would you confirm the diagnosis of herpes hepatitis?
Answer Q4

Diagnosis is difficult given the lack of specific findings such as herpetic lesions. Additional challenges come from the lack of rapid diagnostic modalities for HSV. Currently, the major laboratory tests used for diagnosis of HSV are herpes virus serology, liver biopsy, viral culture, antigen detection tests (enzyme immunoassay or immunofluorescence on smears), and nucleic acid detection with polymerase chain reaction. Viral cultures are extremely sensitive and can be used as a screening tool but are very poorly specific and not readily available. Viral PCR testing may be useful but is often not rapidly available. Although not always possible due to coagulopathy, the gold standard for diagnosis is liver biopsy. In addition, laboratory investigations often show leukopenia, thrombocytopenia, and coagulopathy. Renal failure is not uncommon in these patients. Disseminated intravascular coagulopathy is frequently reported, and encephalopathy is a late sign of the disease. Ninety per cent of patients with HSV hepatitis have a characteristic liver profile, known as “anicteric hepatitis”. There may be a marked elevation of AST greater than ALT.

Question 5 What is the treatment of herpes hepatitis?
Answer to Q5

A recent analysis of 137 patients suggested that treatment with acyclovir, if instituted early, may reverse disease and avoid the need for liver transplantation. In treated patients, the mean time from overt symptoms to treatment with acyclovir was 4.2±1.8 days. There was a delay in the initiation of treatment (mean 4.7 vs. 3.5 days, p=0.03) in patients who died or required liver transplantation as compared to patients who survived. Acyclovir is classified as a category B drug in pregnancy with no fetal risk demonstrated in animal or human studies. In addition, acyclovir is easy to administer and has few side effects. The question of the safety of acyclovir in pregnancy has been reinforced in multiple studies where the rates of birth defects (2.6%) were not different from the expected rate (3.2%) in the general population. Future studies to evaluate the cost effectiveness of empirical treatment and outcome should be investigated. A 5–7-day course of intravenous acyclovir is currently recommended for most herpes simplex infections, unless HSV encephalitis is diagnosed in which treatment should be extended to 21 days.
References
  1. Udayakumar Navaneethan, Elisha Lancaster, Preethi GK Venkatesh, Jiang Wang, Guy W Neff. Herpes Simplex Virus Hepatitis - It’s High Time We Consider Empiric Treatment. J Gastrointestin Liver Dis; 1March 2011 Vol. 20 No 1, 93-96
  2. Norvell JP, Blei AT, Jovanovic BD, Levitsky J. Herpes simplex virushepatitis: an analysis of the published literature and institutional cases. Liver Transpl 2007; 13:1428-1434.
  3. Rachel A. Poley, Jaime F. Snowdon, and DanielW. Howes. Herpes Simplex Virus Hepatitis in an Immunocompetent Adult: A Fatal Outcome due to Liver Failure. Case Reports in Critical Care Volume 2011, Article ID 138341
  4. Lawrence S Friedman, MD. Approach to the patient with abnormal liver biochemical and function tests. Up To Date, accessed 25/01/2017
  5. T. H. Flewett, R. G. Parker, and W. M. Philip, “Acute hepatitis due to Herpes simplex virus in an adult,” Journal of Clinical Pathology, vol. 22, no. 1, pp. 60–66, 1969.
  6. J. Levitsky, A. T. Duddempudi, F. D. Lakeman et al., “Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure,” Liver Transplantation, vol. 14, no. 10, pp.1498–1504, 2008
  7. K. A. Workowski and S. Berman, “Sexually transmitted diseases treatment guidelines, 2010,” Morbidity and Mortality Weekly Report. Recommendations and Reports, vol. 59, no. 12, pp. 1–110,2010.

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