Herpes simplex virus hepatitis: An analysis of the published literature and institutional cases
Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation (LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were identified. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash was seen in less than half of patients. Most cases (58%) were first diagnosed at autopsy and the diagnosis was suspected clinically prior to tissue confirmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-treated patients as compared to 88% in the untreated subjects (P=0.03). Variables on presentation associated with death or need for LT compared to spontaneous survival: male gender, age>40 yr, immunocompromised state, ALT>5,000 U/L, platelet count<75x10(3)/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with significant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the frequent delay in HSV diagnosis, low risk-benefit ratio, and significantly improved outcomes, empiric acyclovir therapy for patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded.
Herpes Simplex Virus Hepatitis: An Analysis of
the Published Literature and Institutional Cases
John P. Norvell,
Andres T. Blei,
Borko D. Jovanovic,
and Josh Levitsky
Department of Internal Medicine, Division of Hepatology, Northwestern University Feinberg School of
Medicine, Chicago, IL;
Department of Preventive Medicine, Northwestern University Feinberg School of
Medicine, Chicago, IL
Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation
(LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an
analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were
identiﬁed. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash
was seen in less than half of patients. Most cases (58%) were ﬁrst diagnosed at autopsy and the diagnosis was suspected
clinically prior to tissue conﬁrmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-
treated patients as compared to 88% in the untreated subjects (P ⫽ 0.03). Variables on presentation associated with death or
need for LT compared to spontaneous survival: male gender, age ⬎40 yr, immunocompromised state, ALT ⬎5,000 U/L,
platelet count ⬍75 ⫻ 10
/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has
a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with
signiﬁcant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the
frequent delay in HSV diagnosis, low risk-beneﬁt ratio, and signiﬁcantly improved outcomes, empiric acyclovir therapy for
patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded. Liver Transpl 13:
© 2007 AASLD.
Received March 11, 2007; accepted May 24, 2007.
First described in adults in 1969,
virus (HSV) hepatitis is an uncommon complication of
HSV infection often leading to acute liver failure (ALF).
It is thought to represent less than 1% of all ALF cases
and less than 2% of all viral causes of ALF.
commonly affected individuals are immunosuppressed
patients and females in the third trimester of preg-
nancy, although HSV hepatitis can occur in immuno-
competent patients. HSV hepatitis is characterized by
fulminant hepatic necrosis with serum aminotransfer-
ase levels 100 to 1,000-fold above normal. The diagno-
sis is frequently made at postmortem examination due
to the nonspeciﬁc clinical presentation and lack of
awareness. In one series, the diagnosis of HSV hepatitis
was considered antemortem in only 33% of pregnant
patients and 26% of nonpregnant patients.
patients with HSV hepatitis have mucocutaneous le-
sions that provide clinical clues to the diagnosis.
Despite the high morbidity and mortality, HSV hepa-
titis is a potentially treatable disorder if recognized and
treated expeditiously. A high degree of suspicion, even
in the absence of skin lesions, combined with early
diagnostic modalities (serology, polymerase chain reac-
tion, liver biopsy) may dramatically improve survival.
Treatment with parenteral acyclovir may reverse the
disease process if instituted early.
on presentation and during the course of disease would
be of great use to clinicians in determining the likeli-
hood of clinical progression, need for liver transplanta-
tion (LT), or spontaneous recovery.
data and knowledge on HSV hepatitis has originated
from multiple case reports, this article represents a
Abbreviations: HSV, herpes simplex virus; ALF, acute liver failure; LT, liver transplantation; OR, odds ratio; CI, conﬁdence interval;.
Address reprint requests to Josh Levitsky, M.D., Assistant Professor of Medicine, Northwestern University Feinberg School of Medicine,
Department of Medicine, Division of Hepatology, 675 N. St. Clair St. Suite 15-250, Chicago, IL 60611. Telephone: 312-695-4413; FAX:
312-695-5998; E-mail: firstname.lastname@example.org
Published online in Wiley InterScience (www.interscience.wiley.com).
LIVER TRANSPLANTATION 13:1428-1434, 2007
© 2007 American Association for the Study of Liver Diseases.
comprehensive analysis of all the documented adult
cases of HSV hepatitis from our center and in the liter-
ature to determine patient characteristics and prognos-
tic factors associated with important outcomes.
A retrospective review of our institution’s electronic
chart and pathology databases (established in 1995)
revealed 5 previously unreported cases of HSV hepati-
tis. A comprehensive search of the National Library of
Medicine PubMed database (1969-2006) revealed 89
publications involving 132 additional case reports of
HSV hepatitis. The following National Library of Medi-
cine MEDLINE subject heading (MeSH) terms were
matched to search for cases in PubMed: “herpes sim-
plex virus,” “hepatitis virus,” “hepatitis,” “acute hepatic
failure,” and “fulminant liver failure.” The criteria for
inclusion of cases were patients aged 18 yr or older,
evidence of hepatocellular injury, and histological evi-
dence of HSV hepatitis. If no liver histology was ob-
tained by biopsy or autopsy, the case was included only
if the article provided evidence of HSV hepatitis by all of
the following 3 clinical criteria: 1) serology or biopsy of
nonhepatic tissue consistent with active HSV infection;
2) peak aminotransferase ⬎500 U/L; and 3) no other
attributable cause of ALF. A total of 6 articles with case
reports were excluded due to insufﬁcient evidence of
HSV hepatitis. This study was approved by the North-
western University Institutional Review Board.
Of the included cases, univariate logistic regression
was performed to determine which of the following vari-
ables on presentation were associated with either sur-
vival or death/LT: age, gender, immunosuppression,
liver/renal function, coagulopathy, hepatic encepha-
lopathy, and subsequent antiviral therapy. Multivariate
analysis was performed, but due to missing values in
the data from the retrospective collection of literature
cases, the joint estimators of risk were judged to be not
reliable. A univariate analysis was also performed to
determine differences in clinical characteristics among
acyclovir treated and untreated patients. Chi-squared
and Mann-Whitney 2-sample rank sum tests were used
in this analysis for categorical and continuous vari-
ables, respectively. All P values are 2-sided and were
considered signiﬁcant if less than 0.05. Statistical anal-
ysis was performed using the Intercooled STATA system
for Windows, version 9.2 (StataCorpLP, College Station,
Clinical Presentation (Northwestern and
Table 1 displays the clinical presentation and outcome
of previously unreported cases presenting at our hos-
pital with HSV hepatitis. Table 2 shows the combined
clinical characteristics, when reported, of all patients in
the literature and our hospital presenting with HSV
Of note, 24% were considered immu
nocompetent. The remaining patients were either preg-
nant (23%) or immunocompromised from a previous
solid organ or hematopoietic cell transplantation (30%)
or immunosuppressive agent (23%). Of the immuno-
compromised patients from prior transplantation, the
average time of disease onset after transplantation was
205 days (⫾526). 98% of the patients had fever. Her-
petic rash was detected in only 44% of patients, of
which 61% were mucocutaneous and 39% were dis-
seminated. The majority developed coagulopathy
(96.5%), encephalopathy (80%), and acute renal failure
Table 3 demonstrates the method of diagnosis for the
137 cases. The majority was ﬁrst diagnosed after death
on autopsy (57.6%); 31.4% were diagnosed by liver bi-
opsy. Of the patients ﬁrst diagnosed by autopsy, only 8
TABLE 1. Characteristics of Northwestern HSV Hepatitis Cases
gender Predisposing factors
(mg/dL) Rash Treatment
1: 44, female None 6,000 7.1 24.4 Disseminated ACV ⫻ 11 days
prior to LKT
2: 31, male PNH, stem cell
13,955 2.5 2.5 None ACV ⫻ 6 days Liver biopsy,
3: 29, female UC, steroids after
2,097 3 8.1 None ACV ? duration Liver biopsy Survived
4: 59, female Multiple myeloma,
4,531 3.5 7.7 None None Autopsy Died
5: 43, male CML, bone marrow
3,349 1.8 34.5 None GCV ⫻ 5 days Liver biopsy Died
Abbreviations: ACV, acyclovir; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CML, chronic myelogenous
leukemia; GCV, ganciclovir; INR, international normalized ratio; LKT, liver-kidney transplantation; PNH, paroxysmal
nocturnal hemoglobinuria; TB, total bilirubin; UC, ulcerative colitis.
HERPES SIMPLEX VIRUS HEPATITIS 1429
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
were suspected clinically prior to death. A total of 11
patients (8%) included in this series never had HSV
hepatitis conﬁrmed by liver biopsy or autopsy but met
our 3 clinical criteria.
31 (22.6%) of the 137 cases were ﬁrst suspected clini-
cally by the patient’s history and presentation. Of these
cases, the diagnosis was conﬁrmed by autopsy in 8,
liver biopsy in 10, and explanted liver in 2.
Treatment and Outcomes
A total of 49 (36.6%) of 134 patients were given paren-
teral acyclovir. It was unclear whether acyclovir was
administered or not in 3 patients. As a result, they were
removed from the analysis. Table 4 displays the com-
parison of clinical characteristics and outcome (when
reported) of acyclovir-treated and untreated patients.
Other than age being lower in treated patients, no other
variables on clinical presentation were different be-
tween the groups. For outcomes, the percentage of
treated patients progressing to death or LT was signif-
icantly lower (51%) compared to untreated patients
(88.1%) (P ⬍ 0.001). Of the 34 cases with sufﬁcient
clinical information, the mean time from overt symp-
toms of HSV hepatitis to treatment with acyclovir was
4.2 days (standard deviation ⫽ 1.8). A signiﬁcantly
longer time from symptom onset to treatment initiation
(mean 4.7 ⫾ .48 vs. 3.5 ⫾ .27 days) was seen in patients
who died or required LT compared to those who sur-
vived (P ⫽ 0.03).
A total of 7 patients underwent orthotopic LT for ful-
minant liver failure with 3 ultimately surviving. The
causes of death in the 4 patients are the following:
hemothorax (29 days after LT),
acute respiratory dis
tress syndrome (11 days after LT),
days after LT, Northwestern patient #1, no autopsy),
and recurrent HSV and multiorgan failure despite con-
tinuous parenteral acyclovir (42 days after LT).
remaining patients survived long-term (mean reported
follow-up ⫽ 989 days, standard deviation ⫽ 1,448
days). Two patients developed HSV rash within 2 weeks
of discontinuing acyclovir but neither developed dis-
seminated HSV (Northwestern patient #1).
sponded to intravenous acyclovir. Two patients devel-
TABLE 2. Demographics and Clinical Presentation of
Mean age (yr) 34 ⫾ 15
Male 51/137 (38)
Female 82/137 (62)
Immunocompetent 33/137 (24)
Immunosuppressed, total 73/137 (53)
Immunosuppressed, transplant 41/137 (30)
Immunosuppressed, nontransplant 32/137 (23)
Pregnant 32/137 (23)
Fever 98/100 (98)
Herpetic lesions (initial or during
None 69/123 (56)
Mucocutaneous 33/123 (27)
Disseminated 21/123 (17)
Mean peak ALT or AST (U/L) 4927 ⫾ 4099
Mean peak total bilirubin (mg/dL) 6.0 ⫾ 8.1
Leukopenia 50/70 (71.4)
Thrombocytopenia 59/63 (93.6)
Acute renal failure 34/52 (65.3)
Hepatic encephalopathy 57/71 (80)
Type I 36/93 (38.7)
Type II 57/93 (61.3)
Abbreviations: ALT, alanine aminotransferase; AST,
TABLE 3. Diagnosis and Outcomes of HSV Hepatitis
Method of initial diagnosis
Autopsy 79/137 (57.6)
Liver biopsy 43/137 (31.4)
Explanted liver 4/137 (2.9)
Clinical criteria 11/137 (8.0)
Clinical suspicion on initial
presentation 31/137 (22.6)
Conﬁrmed by liver biopsy 10/137 (7.3)
Conﬁrmed by explanted liver 2/137 (1.5)
Conﬁrmed by autopsy 8/137 (5.8)
Conﬁrmed by clinical criteria 11/137 (8.0)
Acyclovir treatment 49/134 (36.6)
Reason for acyclovir treatment
Clinical suspicion 23/49 (46.9)
Serological conﬁrmation 4/49 (8.2)
Liver biopsy conﬁrmation 22/49 (44.9)
Overall 99/133 (74.4)
Liver transplant 4/7 (57.1)
TABLE 4. Acyclovir-Treated and Untreated Group
Acyclovir No acyclovir
Mean age (yr)* 32.9 ⫾ 11.3 40 ⫾ 18.1
Male gender (%) 15/49 (30.1) 35/84 (41.6)
Coagulopathy (%) 35/44 (79.5) 57/66 (86.4)
Immunocompromised (%) 25/49 (51) 45/84 (53.6)
Encephalopathy (%) 21/25 (84) 36/46 (78.3)
Rash (%) 19/44 (43.2) 35/78 (44.8)
Mean ALT or AST (U/L) 4398 ⫾ 3668 5263 ⫾ 4375
Mean bilirubin (mg/dL) 7.8 ⫾ 10.8 3.7 ⫾ 4.1
Mean platelet (10
68 ⫾ 62 52⫾39
25/49 (51) 74/84 (88.1)
Abbreviations: ALT, alanine aminotransferase; AST,
*P ⫽ 0.03.
P ⬍ 0.001.
1430 NORVELL ET AL.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
oped acute cellular rejection within 2 weeks of LT,
1 required retransplantation
and both survived.
Death/Liver Transplantation vs. Survival
On univariate logistic regression, the following vari-
ables were statistically associated with death or need
for LT compared to spontaneous recovery: age ⬎ 40 yr
old (odds ratio [OR], 2.9; 95% conﬁdence interval [CI],
1.2-7.5), male gender (OR, 6.9; 95% CI, 2.3-21.1), co-
agulopathy (OR, 21.5; 95% CI, 6.1-75.7), any immuno-
compromised state (OR, 2.3; 95% CI, 1.4-5.0), enceph-
alopathy (OR, 11.0; 95% CI, 2.9-41.5), ALT ⬎5,000 U/L
(OR, 9.3; 95% CI, 2.6-33.6), platelet count ⬍75,000 U
(OR, 15.5; 95% CI, 3.6-67.3), and acyclovir treatment
(OR, 0.14; 95% CI, 0.06-0.33).
We performed a retrospective analysis on the presenta-
tion and outcomes of all cases of HSV hepatitis reported
in the literature and at our institution. Common fea-
tures on presentation included fever, high amin-
otransferases, leukopenia, thrombocytopenia, en-
cephalopathy, coagulopathy, and acute renal failure.
On regression analysis, older age, male gender, immu-
nocompromised state, the degree of aminotransferase
elevation, and the presence of coagulopathy and en-
cephalopathy were signiﬁcantly associated with pro-
gression of disease to death or need for LT. These clin-
ical predictors should highlight the need for early
treatment and immediate LT evaluation to increase sur-
Interestingly, almost 25% of the patients were con-
sidered immunocompetent prior to the onset of HSV
hepatitis. While multiple mechanisms of disseminated
infection have been proposed in immunocompromised
hosts, it remains unclear why a signiﬁcant proportion is
seemingly immunocompetent. Theories include a high
inoculation of HSV viremia at initial infection that over-
comes immunological defenses, occult defects in T lym-
phocytes and/or macrophages processing HSV anti-
gen, reinfection by a second strain increasing HSV
virulence, or speciﬁc hepatovirulent strains of HSV.
This review highlights the challenge in diagnosing
HSV hepatitis. The characteristic rash occurred in less
than half of the cases. Most were not diagnosed until
after death and only 23% were clinically suspected to
have HSV hepatitis prior to histological conﬁrmation.
Given the absence of clinical clues and need for rapid
diagnosis, HSV should be universally screened for
when a patient presents with acute hepatitis or liver
failure, particularly with fever on presentation. A pelvic
examination should be performed as many women have
vaginal and cervical involvement in the absence of more
obvious vulvar involvement.
Results of Tzanck smear
or direct ﬂuorescent antibody staining can be available
quickly and guide management.
Serologic testing is
limited due to a high rate of false-positive and false-
negative tests. Recent attention has focused on quan-
titative HSV deoxyribonucleic acid by polymerase chain
reaction as a diagnostic modality, although this is only
performed in reference laboratories and the results may
not be available for real-time decision making pro-
cesses. Without a rapid polymerase chain reaction
available, liver biopsy should be considered early in the
course of hepatitis. It is the gold standard test but is
also underutilized, being performed in less than one-
third of patients in our study. The use of recombinant
factor VII, while expensive, may provide reversal of co-
agulopathy in ALF and safely allow such invasive pro-
Despite a high mortality, HSV hepatitis is one of the
few treatable causes of ALF, reemphasizing the need for
early diagnosis. Our results show a signiﬁcantly lower
rate of progression to death or LT in acyclovir-treated
patients compared to untreated. Other than being
somewhat younger, treated patients were similar to un-
treated patients in clinical characteristics and severity
of liver failure on presentation, suggesting that acyclo-
vir treatment was the major independent factor leading
to increased survival. In addition, an early diagnosis
with a shorter time delay from symptom onset to initi-
ation of treatment was signiﬁcantly associated with
survival. It is clear that patients need to be diagnosed
and treated early to have an impact on recovery and
For progressive liver failure, LT may be a viable option
in the setting of pre- and posttransplantation acyclovir
therapy. Three of 7 patients survived long-term without
recurrent HSV hepatitis or dissemination. Of the 4 who
died post-LT, only 1 had recurrent HSV as a potential
contributor to death.
That being said, the high mor
bidity and mortality after LT is not insigniﬁcant. Life-
long antiviral therapy after LT is likely required to pre-
vent recurrences, as 2 of the patients had recurrent
rash within 2 weeks of acyclovir discontinuation. Point
mutations in the viral thymidine kinase, however, may
result in failure to clear viral replication, resulting in
acyclovir resistance. It is speculated that the relatively
high frequency of acyclovir resistant herpes viruses in
immunocompromised patients may be due to an im-
paired T-cell response.
There are limitations of this study. The retrospective
design is limited by the accuracy and completeness of
the data reported in the literature and from our hospital
records. Some of the data regarding the aspects of clin-
ical presentation and treatment were not presented in
the case series. This may have affected the ability to
determine other important variables associated with
progressive disease and perform a multivariate analy-
sis. In addition, only severe cases of herpes hepatitis
are likely to have been reported in the literature, leading
to selection bias. It is possible that cases of clinically
less severe HSV hepatitis have occurred and were not
reported, although all of the cases at our institution
presented with severe liver failure. Nevertheless, it is
likely that the included literature and institutional
cases represent the typical clinical spectrum. Finally,
this series includes 11 patients who met our clinical
inclusion criteria for HSV hepatitis without liver histol-
HERPES SIMPLEX VIRUS HEPATITIS 1431
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
ogy conﬁrmation. While no other etiologies were identi-
ﬁed and the presentations were highly suggestive of
HSV hepatitis, it is possible that another etiology was
responsible for ALF.
Given our ﬁndings, speciﬁc guidelines for the diagno-
sis and treatment of HSV hepatitis are recommended. It
is imperative that HSV is considered in the differential
diagnosis of a patient presenting with ALF, particularly
when fever is present. The absence of a vesicular rash
should not lower the physician’s index of suspicion for
HSV. Virological testing, such as quantitative HSV
deoxyribonucleic acid, should be sent immediately to
a laboratory providing a quick return of results. A
transjugular liver biopsy should be considered after
correction of coagulation disturbances. Based on the
low risk-beneﬁt ratio and frequently-delayed diagnosis,
our data supports the practice of empiric treatment
with parenteral acyclovir for all patients presenting
with ALF of unknown etiology, until an alternative di-
agnosis is made or HSV is excluded. For those with risk
factors for progression on initial presentation, e.g.,
male gender, advanced age, immunosuppression, and
signiﬁcant biochemical liver dysfunction, an urgent LT
evaluation should be considered early to maximize sur-
vival. While outcomes are not ideal, LT can be per-
formed successfully in select patients.
1. Flewett TH, Parker RG, Philip WM. Acute hepatitis due to
Herpes simplex virus in an adult. J Clin Pathol 1969;22:
2. Chase RA, Pottage JC Jr, Haber MH, Kistler G, Jensen D,
Levin S. Herpes simplex viral hepatitis in adults: two case
reports and review of the literature. Rev Infect Dis 1987;
3. Schiodt F DT, Shakil O, McGuire B, Samuel G, Lee W, the
Acute Liver Failure Study Group. Viral hepatitis-related
acute liver failure. Am J Gastroenterol 2003;98:448-453.
4. Aboguddah A, Stein HB, Phillips P, Amar J, English R.
Herpes simplex hepatitis in a patient with psoriatic arthri-
tis taking prednisone and methotrexate. Report and review
of the literature. J Rheumatol 1991;18:1406-1412.
5. Velasco M, Llamas E, Guijarro-Rojas M, Ruiz-Yague M.
Fulminant herpes hepatitis in a healthy adult: a treatable
disorder? J Clin Gastroenterol 1999;28:386-389.
6. Chung AB, Fas N. Successful acyclovir treatment of herpes
simplex type 2 hepatitis in a patient with systemic lupus
erythematosus: a case report and metaanalysis. Am J Med
7. Diderholm H, Stenram U, Tegner KB, Willen R. Herpes
simplex hepatitis in an adult. A case report with virological
and electron microscopical examination at autopsy. Acta
Med Scand 1969;186:151-155.
8. Foley FD, Greenawald KA, Nash G, Pruitt BA Jr. Herpes-
virus infection in burned patients. N Engl J Med 1970;282:
9. Dowling JN, Henry. Non-responsive coeliac disease. Br
Med J 1972;3:624-631.
10. Francis TI, Osuntokun BO, Kemp GE. Fulminant hepatitis
due to herpes hominis in an adult human. Am J Gastro-
11. Lee JC, Fortuny IE. Adult herpes simplex hepatitis. Hum
12. Goyette RE, Donowho EM Jr, Hieger LR, Plunkett GD.
Fulminant herpesvirus hominis hepatitis during preg-
nancy. Obstet Gynecol 1974;43:191-195.
13. Orenstein JM, Castadot MJ, Wilens SL. Fatal herpes hep-
atitis associated with pemphigus vulgaris and steroids in
an adult. Hum Pathol 1974;5:489-493.
14. Sutton AL, Smithwick EM, Seligman SJ, Kim DS. Fatal
disseminated herpesvirus hominis type 2 infection in an
adult with associated thymic dysplasia. Am J Med 1974;
15. Anuras S, Summers R. Fulminant herpes simplex hepati-
tis in an adult: report of a case in renal transplant recip-
ient. Gastroenterology 1976;70:425-428.
16. Eron L, Kosinski K, Hirsch MS. Hepatitis in an adult
caused by Herpes simplex virus type I. Gastroenterology
17. Keane JT, Malkinson FD, Bryant J, Levin S. Herpesvirus
hominis hepatitis and disseminated intravascular coagu-
lation. Occurrence in an adult with pemphigus vulgaris.
Arch Intern Med 1976;136:1312-1317.
18. Young EJ, Killam AP, Greene JF Jr. Disseminated herpes-
virus infection. Association with primary genital herpes in
pregnancy. JAMA 1976;235:2731-2733.
19. Abraham AA, Manko MA. Disseminated Herpesvirus
hominis 2 infection following drug overdose. Arch Intern
20. Mozes MF, Ascher NL, Balfour HH Jr, Simmons RL, Naja-
rian JS. Jaundice after renal allotransplantation. Ann
21. Connor RW, Lorts G, Gilbert DN. Lethal herpes simplex
virus type 1 hepatitis in a normal adult. Gastroenterology
22. Hensleigh PA, Glover DB, Cannon M. Systemic Herpesvi-
rus hominis in pregnancy. J Reprod Med 1979;22:171-
23. Sullivan SN. Herpes simplex hepatitis. Gastroenterology
24. Elliott WC, Houghton DC, Bryant RE, Wicklund R, Barry
JM, Bennett WM. Herpes simplex type 1 hepatitis in renal
transplantation. Arch Intern Med 1980;140:1656-1660.
25. Bernuau J, Rueff B, Clauvel JP, Degott C, Perol Y, Ben-
hamou JP. Non-inﬂammatory herpes simplex hepatitis in
an adult with chronic neutropenia. Liver 1981;1:244-248.
26. Hamory BH, Luger A, Kobberman T. Herpesvirus hominis
hepatitis of mother and newborn infant. South Med J
27. Taylor RJ, Saul SH, Dowling JN, Hakala TR, Peel RL, Ho
M. Primary disseminated herpes simplex infection with
fulminant hepatitis following renal transplantation. Arch
Intern Med 1981;141:1519-1521.
28. Walker DP, Longson M, Lawler W, Mallick NP, Davies JS,
Johnson RW. Disseminated herpes simplex virus infection
with hepatitis in an adult renal transplant recipient. J Clin
29. Berglin E, Blohme I, Frisk B, Hedman L, Jeansson S,
Brynger H. A case of lethal herpes simplex hepatitis in a
diabetic renal transplant recipient. Transplant Proc 1982;
30. Hillard P, Seeds J, Cefalo R. Disseminated herpes simplex
in pregnancy: two cases and a review. Obstet Gynecol
31. Marrie TJ, McDonald AT, Conen PE, Boudreau SF. Herpes
simplex-hepatitis use of immunoperoxidase to demon-
strate the viral antigen in hepatocytes. Gastroenterology
32. Schneider V, Behm FG, Mumaw VR. Ascending herpetic
endometritis. Obstet Gynecol 1982;59:259-262.
33. Haboubi NY, Sutton RN, Craske J, Roberts J. Dissemi-
nated herpes simplex virus infection with misleading clin-
ical presentation. J Clin Pathol 1983;36:115-116.
1432 NORVELL ET AL.
34. Peacock JE Jr, Sarubbi FA. Disseminated Herpes simplex
virus infection during pregnancy. Obstet Gynecol 1983;
35. Wertheim RA, Brooks BJ Jr, Rodriguez FH Jr, Lesesne HR,
Jennette JC. Fatal herpetic hepatitis in pregnancy. Obstet
36. Whorton CM, Thomas DM, Denham SW. Fatal systemic
herpes simplex virus type 2 infection in a healthy young
woman. South Med J 1983;76:81-83.
37. Lagrew DC Jr, Furlow TG, Hager WD, Yarrish RL. Dissem-
inated herpes simplex virus infection in pregnancy. Suc-
cessful treatment with acyclovir. JAMA 1984;252:2058-
38. Fisher NA, Iwata RT, Eger EI 2nd, Smuckler EA. Hepatic
necrosis associated with herpes virus after isoﬂurane an-
esthesia. Anesth Analg 1985;64:1131-1133.
39. Goyert GL, Bottoms SF, Sokol RJ. Anicteric presentation
of fatal herpetic hepatitis in pregnancy. Obstet Gynecol
40. Rakela J, Lange SM, Ludwig J, Baldus WP. Fulminant
hepatitis: Mayo Clinic experience with 34 cases. Mayo Clin
41. Rubin MH, Ward DM, Painter CJ. Fulminant hepatic fail-
ure caused by genital herpes in a healthy person. JAMA
42. Williams TL, Morgan JR, Denzler TB. Fulminant herpes
simplex hepatitis following coronary bypass and postcar-
diotomy syndrome. Am Heart J 1985;110:679-680.
43. Baxter RP, Phillips LE, Faro S, Hoffman L. Hepatitis due to
herpes simplex virus in a nonpregnant patient: treatment
with acyclovir. Sex Transm Dis 1986;13:174-176.
44. Goodman ZD, Ishak KG, Sesterhenn IA. Herpes simplex
hepatitis in apparently immunocompetent adults. Am J
Clin Pathol 1986;85:694-699.
45. Andre PM, Camus C, Ruffault A, Cartier F. Herpes hepa-
titis and high levels of circulating interferon. J Infect Dis
46. Chazotte C, Andersen HF, Cohen WR. Disseminated her-
pes simplex infection in an immunocompromised preg-
nancy: treatment with intravenous acyclovir. Am J Peri-
47. Gabel H, Flamholc L, Ahlfors K. Herpes simplex virus
hepatitis in a renal transplant recipient: successful treat-
ment with acyclovir. Scand J Infect Dis 1988;20:435-438.
48. Groza S, Delic D, Zerjav S, Jovanovic R, Bujko M. Recovery
from herpes simplex virus type-1 hepatitis in a female
adult. Klin Wochenschr 1988;66:796-798.
49. Koneru B, Tzakis AG, DePuydt LE, Demetris AJ, Arm-
strong JA, Dummer JS, Starzl TE. Transmission of fatal
herpes simplex infection through renal transplantation.
50. Singh N, Dummer JS, Kusne S, Breinig MK, Armstrong
JA, Makowka L, et al. Infections with cytomegalovirus and
other herpesviruses in 121 liver transplant recipients:
transmission by donated organ and the effect of OKT3
antibodies. J Infect Dis 1988;158:124-131.
51. Zimmerli W, Bianchi L, Gudat F, Spichtin H, Erb P, von
Planta M, Heitz PU. Disseminated herpes simplex type 2
and systemic Candida infection in a patient with previous
asymptomatic human immunodeﬁciency virus infection.
J Infect Dis 1988;157:597-598.
52. McMinn PC, Lim IS, McKenzie PE, van Deth AG, Simmons
A. Disseminated herpes simplex virus infection in an ap-
parently immunocompetent woman. Med J Aust 1989;
151:588-590, 592, 594.
53. Klein NA, Mabie WC, Shaver DC, Latham PS, Adamec TA,
Pinstein ML, Riely CA. Herpes simplex virus hepatitis in
pregnancy. Two patients successfully treated with acyclo-
vir. Gastroenterology 1991;100:239-244.
54. Kusne S, Schwartz M, Breinig MK, Dummer JS, Lee RE,
Selby R, et al. Herpes simplex virus hepatitis after solid
organ transplantation in adults. J Infect Dis 1991;163:
55. Miyazaki Y, Akizuki S, Sakaoka H, Yamamoto S, Terao H.
Disseminated infection of herpes simplex virus with ful-
minant hepatitis in a healthy adult. A case report. APMIS
56. Tomita T, Chiga M, Lenahan M, Balachandran N. Identi-
ﬁcation of herpes simplex virus infection by immunoper-
oxidase and in situ hybridization methods. Virchows Arch
A Pathol Anat Histopathol 1991;419:99-105.
57. Jacques SM, Qureshi F. Herpes simplex virus hepatitis in
pregnancy: a clinicopathologic study of three cases. Hum
58. Johnson JR, Egaas S, Gleaves CA, Hackman R, Bowden
RA. Hepatitis due to herpes simplex virus in marrow-
transplant recipients. Clin Infect Dis 1992;14:38-45.
59. Tomita T, Garcia F, Mowry M. Herpes simplex hepatitis
before and after acyclovir treatment. Immunohistochemi-
cal and in situ hybridization study. Arch Pathol Lab Med
60. Fink CG, Read SJ, Hopkin J, Peto T, Gould S, Kurtz JB.
Acute herpes hepatitis in pregnancy. J Clin Pathol 1993;
61. Lasserre M, Huguet C, Terno O. Acute severe herpes sim-
plex hepatitis with virus-associated hemophagocytic syn-
drome in an immunocompetent adult. J Hepatol 1993;18:
62. Mudido P, Marshall GS, Howell RS, Schmid DS, Steger S,
Adams G. Disseminated herpes simplex virus infection
during pregnancy. A case report. J Reprod Med 1993;38:
63. Takebe N, Yokoyama A, Akasaka Y, Ishii H, Miyaguchi S,
Sata T, et al. Fatal herpes simplex hepatitis type 2 in a
post-thymectomized adult. Gastroenterol Jpn 1993;28:304-
64. Wolfsen HC, Bolen JW, Bowen JL, Fenster LF. Fulminant
herpes hepatitis mimicking hepatic abscesses. J Clin Gas-
65. Greenspoon JS, Wilcox JG, McHutchison LB, Rosen DJ.
Acyclovir for disseminated herpes simplex virus in preg-
nancy. A case report. J Reprod Med 1994;39:311-317.
66. Johnson LG, Saldana LR. Herpes simplex virus hepatitis
in pregnancy. A case report. J Reprod Med 1994;39:544-
67. McCalmont TH, McLeod DL, Kerr RM, Hopkins MB, Geis-
inger KR. Fatal disseminated herpesvirus infection with
hepatitis. A peritoneal ﬂuid cytologic warning. Arch Pathol
Lab Med 1994;118:566-567.
68. Shanley CJ, Braun DK, Brown K, Turcotte JG, Greenson
JK, Beals TF, et al. Fulminant hepatic failure secondary
to herpes simplex virus hepatitis. Successful outcome
after orthotopic liver transplantation. Transplantation
69. Gelven PL, Gruber KK, Swiger FK, Cina SJ, Harley RA.
Fatal disseminated herpes simplex in pregnancy with ma-
ternal and neonatal death. South Med J 1996;89:732-
70. Glorioso DV, Molloy PJ, Van Thiel DH, Kania RJ. Success-
ful empiric treatment of HSV hepatitis in pregnancy. Case
report and review of the literature. Dig Dis Sci 1996;41:
71. Young EJ, Chaﬁzadeh E, Oliveira VL, Genta RM. Dissem-
inated herpesvirus infection during pregnancy. Clin Infect
72. Farr RW, Short S, Weissman D. Fulminant hepatitis dur-
ing herpes simplex virus infection in apparently immuno-
competent adults: report of two cases and review of the
literature. Clin Infect Dis 1997;24:1191-1194.
HERPES SIMPLEX VIRUS HEPATITIS 1433
73. Kaufman B, Gandhi SA, Louie E, Rizzi R, Illei P. Herpes
simplex virus hepatitis: case report and review. Clin Infect
74. Yaziji H, Hill T, Pitman TC, Cook CR, Schrodt GR. Gesta-
tional herpes simplex virus hepatitis. South Med J 1997;
75. Gruson D, Hilbert G, Le Bail B, Portel L, Boiron JM, Rei-
ffers J, Gbikpi-Benissan G. Fulminant hepatitis due to
herpes simplex virus-type 2 in early phase of bone marrow
transplantation. Hematol Cell Ther 1998;40:41-44.
76. Kang AH, Graves CR. Herpes simplex hepatitis in preg-
nancy: a case report and review of the literature. Obstet
Gynecol Surv 1999;54:463-468.
77. Seksik P, Gozlan J, Guitton C, Galula G, Maury E, Offen-
stadt G. Fatal herpetic hepatitis in adult following short
corticotherapy: a case report. Intensive Care Med 1999;
78. Fahy RJ, Crouser E, Pacht ER. Herpes simplex type 2
causing fulminant hepatic failure. South Med J 2000;93:
79. Pellise M, Miquel R. Liver failure due to herpes simplex
virus. J Hepatol 2000;32:170.
80. Peters DJ, Greene WH, Ruggiero F, McGarrity TJ. Herpes
simplex-induced fulminant hepatitis in adults: a call for
empiric therapy. Dig Dis Sci 2000;45:2399-2404.
81. Price TM, Harris JB. Fulminant hepatic failure due to
herpes simplex after hysteroscopy. Obstet Gynecol 2001;
82. Toi M, Kuroda N, Tao L, Jin Y, Guo L, Miyazaki E, et al.
Adult-onset herpes simplex virus hepatitis with diffuse
myoﬁbroblastic transformation of hepatic stellate cells (Ito
cells) in non-necrotic areas. Pathol Int 2001;51:288-292.
83. Frederick DM, Bland D, Gollin Y. Fatal disseminated her-
pes simplex virus infection in a previously healthy preg-
nant woman. A case report. J Reprod Med 2002;47:591-
84. Nagappan R, Parkin G, Simpson I, Sievert W. Fulminant
hepatic failure from herpes simplex in pregnancy. Med J
85. Pinna AD, Rakela J, Demetris AJ, Fung JJ. Five cases of
fulminant hepatitis due to herpes simplex virus in adults.
Dig Dis Sci 2002;47:750-754.
86. Bissig KD, Zimmermann A, Bernasch D, Furrer H, Dufour
JF. Herpes simplex virus hepatitis 4 years after liver
transplantation. J Gastroenterol 2003;38:1005-1008.
87. Hofer S, Hunziker S, Tornillo L, Ludwig CU. Fatal herpes
simplex virus hepatitis complicating chemotherapy with
weekly docetaxel. Ann Oncol 2003;14:340.
88. Mortele KJ, Barish MA, Yucel KE. Fulminant herpes hep-
atitis in an immunocompetent pregnant woman: CT im-
aging features. Abdom Imaging 2004;29:682-684.
89. Sharma S, Mosunjac M. Herpes simplex hepatitis in
adults: a search for muco-cutaneous clues. J Clin Gastro-
90. Allen RH, Tuomala RE. Herpes simplex virus hepatitis
causing acute liver dysfunction and thrombocytopenia in
pregnancy. Obstet Gynecol 2005;106:1187-1189.
91. Herget GW, Riede UN, Schmitt-Graff A, Lubbert M, Neu-
mann-Haefelin D, Kohler G. Generalized herpes simplex
virus infection in an immunocompromised patient–report
of a case and review of the literature. Pathol Res Pract
92. Ichai P, Afonso AM, Sebagh M, Gonzalez ME, Codes L,
Azoulay D, et al. Herpes simplex virus-associated acute
liver failure: a difﬁcult diagnosis with a poor prognosis.
Liver Transpl 2005;11:1550-1555.
93. Longerich T, Eisenbach C, Penzel R, Kremer T, Flechten-
macher C, Helmke B, et al. Recurrent herpes simplex virus
hepatitis after liver retransplantation despite acyclovir
therapy. Liver Transpl 2005;11:1289-1294.
94. Luzar B, Ferlan-Marolt V, Poljak M, Sojar V, Stanisavljevic
D, Bukovac T, Markovic S. Acute fatty liver of pregnan-
cy—an underlying condition for herpes simplex type 2
fulminant hepatitis necessitating liver transplantation. Z
95. Montalbano M, Slapak-Green GI, Neff GW. Fulminant he-
patic failure from herpes simplex virus: post liver trans-
plantation acyclovir therapy and literature review. Trans-
plant Proc 2005;37:4393-4396.
96. Smith I PJ, Hunter J. Cervical infection with herpes sim-
plex virus. Lancet 1981;1:1051.
97. Shami V CS, Hespenheide E, Arseneau K, Bickston S,
Macik B. Efﬁcacy and safety of repeated perioperative
doses of recombinant factor VIIa in liver transplantation.
Liver Transpl 2003;11:872-874.
98. Tsochatzis E PG, Elefsiniotis I, Thanelas S, Theodossiades
G, Moulakakis A, Archimandritis A. Prophylactic and
therapeutic use of recombinant activated factor VII in pa-
tients with cirrhosis and coagulation impairment. Dig
Liver Dis 2006.
1434 NORVELL ET AL.