The decedent was a 71-year-old white woman with a history of rheumatoid arthritis and hypothyroidism who was diagnosed in May 2002 as having a T-cell lymphoma, predominantly large-cell type. She had extensive nodal disease in her abdomen. She was treated with a single course of chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), discharged, and then readmitted on May 28, 2003, febrile with a left lower lobe infiltrate and a urinary tract infection. On physical examination, no hepatomegaly or splenomegaly was noted. Laboratory review demonstrated the following values: creatinine, 0.7 mg/dL (62 μmol/L) (reference range [RR], 0.6–1.2 mg/dL [53–106 μmol/L]); calcium, 8.4 mg/dL (2.1 mmol/L) (RR, 8.4–10.6 mg/dL [2.05–2.55 mmol/L]); total bilirubin, 2.4 mg/dL (41 μmol/L) (RR, 0.3–1.1 mg/dL [5–21 μmol/L]) aspartate aminotransferase, 138 U/L (RR, 20–48 U/L); and alanine aminotransferase, 54 U/L (RR, 10–40 U/L). Serologic test results for hepatitis B and C virus and cytomegalovirus (CMV) were negative. She was prescribed antibiotics for treatment of her pneumonia and urinary tract infection. She failed to respond to therapy, and her clinical status continued to deteriorate. After consultation with her family, she was assigned do-not-resuscitate status and was found unresponsive on June 7, 2002.

Major autopsy findings included the following: bilateral pleural effusions (right, 650 mL; left, 500 mL); massive lymphadenopathy involving mediastinal, peribronchial, retroperitoneal, mesenteric, parapancreatic, and parasplenic lymph nodes; organizing mural vegetations in the right atrium; and infarcts in the kidneys and spleen (weight, 400 g). The liver was massively enlarged (2020 g), and there were innumerable irregular, rather ill-defined, yellowish necrotic foci 1 to 4 mm in maximum diameter (Figure 1). Microscopic examination of the liver revealed foci of necrosis distributed in a nonzonal pattern throughout the liver (Figure 2), and there was mild-to-moderate chronic inflammatory infiltrate in portal tracts. At the edge of the necrotic areas, some periportal hepatocytes with multinucleated forms could be identified (Figure 3). The necrotic areas contained hepatocytes with intranuclear eosinophilic inclusions surrounded by a clear halo, with peripheral margination of chromatin (Figure 4). Some hepatocytes contained ground-glass inclusions in the nucleus.

What is your diagnosis?

Herpes simplex virus (HSV) hepatitis is an uncommon complication of adult HSV type 1 and 2 infection. It occurs primarily in patients with impaired immunity or during pregnancy. Impairment of the host's defenses has been found in 85% of the patients.1 In pregnancy, patients with HSV hepatitis typically present in the third trimester (mean gestational age, 30.6 weeks), suggesting that pregnancy may be a relatively immunocompromised state.2 Other conditions predisposing to HSV hepatitis include malignancies, irradiation, severe burns, and renal transplantation.3 In all of these conditions, cellular immunity is compromised.

In this case, the patient had lymphoma and was treated with a single course of chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). The clinical and biological manifestations of hepatitis developed before the administration of chemotherapy, suggesting the lymphoma played an important role in inducing immunosuppression. The chemotherapy may have contributed to the progression of HSV hepatitis.

The typical clinical course of HSV hepatitis is rapid, relentless, and usually fatal. Sometimes, the clinical symptoms begin as a banal febrile illness with slightly elevated liver enzyme levels but rapidly progress to a severe illness with hepatic failure and stupor.4 Mucosal herpetic lesions often provide clues to the diagnosis. However, mucosal lesions have only been seen in 52% to 69% of cases.5,6 The primary site of infection was not known in the present case, and no skin lesions were noted during the illness. Marked elevation of the liver transaminase values, with only a slight increase in the bilirubin level, and leukopenia and thrombocytopenia are frequently seen in herpes hepatitis.6 Kaufman et al7 reviewed 51 cases and found a white blood cell count of less than 5000/mm3 in 43% of patients. In many cases of herpetic hepatitis, abdominal computed tomography (CT) shows multiple low-density lesions in the liver that do not enhance with contrast medium.8 However, these findings are nonspecific and can also be seen in diffuse metastatic disease, multifocal hepatoma, and diffuse hepatitis. The CT of the abdomen in the present case showed that the liver was unremarkable, making it more difficult to arrive at a correct antemortem diagnosis of HSV hepatitis.

The combination of sudden, markedly elevated serum transaminase levels, fever, and leukopenia should call attention to the possible presence of herpes virus hepatitis in the course of disseminated herpes virus infection. The serologic tests can confirm the clinical diagnosis. The differential diagnosis includes viral hepatitis A, B, C, D, and E; adenovirus hepatitis; and CMV hepatitis. The characteristic finding in CMV hepatitis is an enlarged cell (endothelial, hepatocyte, or bile duct epithelium) that contains basophilic granules in the cytoplasm and a swollen nucleus. The morphologic features of adenovirus hepatitis are similar to those seen in herpes simplex infection.9 Immunohistochemical staining for viral antigens will be helpful for the differential diagnosis. Other causes of hepatitis can usually be excluded on the basis of careful history and laboratory studies. Definitive antemortem diagnosis of HSV hepatitis requires liver biopsy. Transjugular liver biopsy may provide a valuable alternative to open liver biopsy in the setting of fulminant hepatic failure with severe coagulopathy. Culture of HSV from liver tissue biopsy specimens also provides a definitive diagnosis.10 

The diagnosis of HSV hepatitis is frequently made only at postmortem examination, most likely due to the nonspecific findings at presentation (such as in our case) and lack of awareness of this disease process. The histologic examination of the liver in this case showed features that are typical of HSV hepatitis and included multifocal necrosis of the hepatocytes with little inflammatory response. At the edge of the necrotic areas, some periportal hepatocytes with multinucleated forms could be identified. The intranuclear eosinophilic inclusion was characteristically surrounded by a clear halo, with a peripheral margination of chromatin (Cowdry type A inclusion). Most showed a ground-glass appearance of the nuclei. Both of the morphologic changes suggested the presence of viral inclusions. Immunohistochemical studies to detect CMV, adenovirus, and HSV were performed, and a strong nuclear positivity for HSV antigens was detected.

In adults, HSV hepatitis is associated with a exceedingly high mortality rate. Aboguddah et al6 found that death occurred in 81% of patients. There is no consensus regarding the treatment of HSV hepatitis. Specific antiviral treatment has been effective in improving the survival of the patients. Acyclovir seems to be the most promising treatment, since it has shown effectiveness in mucocutaneous, genital, and encephalitic HSV infections. In view of the high mortality, HSV hepatitis must be considered early in any case of unexplained fulminant hepatitis. The diagnosis can be promptly confirmed by viral techniques performed on a liver biopsy and blood specimens. In suspicious cases, empirical therapy with acyclovir may improve the prognosis and may be given even without tissue confirmation.

Seksik
,
P.
,
J.
Gozlan
, and
C.
Guitton
.
et al
.
Fatal herpetic hepatitis in adult following short corticotherapy: a case report.
Intensive Care Med
1999
.
25
:
415
417
.
Kang
,
A. H.
and
C. R.
Graves
.
Herpes simplex hepatitis in pregnancy: a case report and review of the literature.
Obstet Gynecol Surv
1999
.
54
:
463
468
.
Luchtrath
,
H.
,
V.
Totovic
, and
F.
De Leon
.
A case of fulminant herpes simplex hepatitis in an adult.
Pathol Res Pract
1984
.
179
:
235
241
.
Gabel
,
H.
,
L.
Flamholc
, and
K.
Ahlfors
.
Herpes simplex virus hepatitis in a renal transplant recipient: successful treatment with acyclovir.
Scand J Infect Dis
1988
.
20
:
435
438
.
Schlien
,
R. D.
,
S.
Meyers
, and
J. A.
Lee
.
et al
.
Fulminant herpes simplex in a patient with ulcerative colitis.
Gut
1988
.
29
:
257
261
.
Aboguddah
,
A.
,
H.
Stein
, and
P.
Phillips
.
et al
.
Herpes simplex hepatitis is a patient with psoriatic arthritis taking prednisone and methotrexate: report and review of the literature.
J Rheumatol
1991
.
18
:
1406
1412
.
Kaufman
,
B.
,
S. A.
Gandhi
, and
E.
Louie
.
et al
.
Herpes simplex hepatitis: case report and review.
Clin Infect Dis
1997
.
24
:
334
338
.
Fahy
,
R. J.
,
E.
Crouser
, and
E. R.
Pacht
.
Herpes simplex type 2 causing fulminant hepatic failure.
South Med J
2000
.
93
:
1212
1216
.
Lucas
,
S. B.
Other viral and infectious diseases and HIV-related liver disease.
In: MacSween RNM, Burt AD, Portmann BC, Ishak KG, Scheuer PJ, Anthony PP, eds. Pathology of the Liver. 4th ed. London, England: Churchill Livingstone; 2002:363–367
.
Shanley
,
C. J.
,
D. K.
Braun
, and
K.
Brown
.
et al
.
Fulminant hepatic failure secondary to herpes simplex virus hepatitis: successful outcome after orthotopic liver transplantation.
Transplantation
1995
.
59
:
145
149
.

Reprints not available from the authors.

Author notes

Corresponding author: Saul Suster, MD, Department of Surgical Pathology, Ohio State University Medical Center, E-411 Doan Hall 410 W 10th Ave, Columbus, OH 43210-1228