Journal of Viral Hepatitis, 1997, 4, 5154

REVIEW ARTICLE

Severe hepatitis E infection during pregnancy

S. H. Hussaini,1 S. J. Skidmore,2 P. Richardson,1 L. M. Sherratt,2 B. T. Cooper3 and J. G. OGrady1
1
Liver Unit, St Jamess University Hospital, Leeds, 2Public Health Laboratory, Heartlands Hospital, Birmingham and 3Gastroenterology Unit, City
Hospital, Birmingham, UK

Received 1 July 1996; accepted for publication 3 September 1996

SUMMARY. In areas with endemic hepatitis E virus
(HEV), acute liver failure secondary to hepatitis E infec-
tion is common in pregnancy and associated with a
mortality rate of up to 20%. However, there is little
information on the clinical course of severe hepatitis E
infection during pregnancy in non-endemic areas such
as the UK. Here we describe two cases of severe hepati-
tis E in pregnancy in patients returning from the Indian
subcontinent. These cases were diagnosed by the detec-
tion of IgM anti-HEV antibody using an enzyme
immunoassay with recombinant hepatitis E viral anti-
gens. The first case describes acute hepatic failure, with
coagulopathy and encephalopathy, warranting inten-
sive therapy and elective ventilation. In the other case,
the patient had severe hepatitis with coagulopathy.
Both cases spontaneously resolved with no foetal loss.
These cases highlight the need for suspicion of HEV
infection in patients returning from endemic areas and
presenting with acute non-A non-B hepatitis, espe-
cially when pregnant. Furthermore, the intensive
treatment of acute liver failure caused by HEV may
reduce the high mortality reported in Asia.
Keywords: acute liver failure, hepatitis E, pregnancy.

INTRODUCTION we know that sporadic cases of HEV associated with

recent travel to endemic areas do occur in the west
Hepatitis E virus (HEV) is a non-enveloped, single-
and are usually self limiting [9].
stranded RNA virus [1], which was responsible for
Acute hepatic failure secondary to HEV is uncom-
30 000 cases of acute jaundice in a large waterborne
mon in the developed world [8,10,11]. Moreover, there
outbreak of hepatitis seen in Dehli in 1956 [2]. Since
is no information on the clinical course of severe hep-
then there have been numerous other epidemics in
atitis caused by HEV in pregnancy in the UK the
Pakistan, south-east Asia, Africa, Mexico and China
group of patients thought to have a high mortality rate.
[3]. Furthermore, sporadic cases have been reported in
Therefore, we describe two such cases diagnosed by an
endemic areas [4].
enzyme immunoassay (EIA) to detect anti-HEV IgM.
The incubation period for HEV ranges from 29
One of these patients had acute hepatic failure.
weeks, affecting predominantly young adults, with
an overall mortality rate of 0.44.0% [3]. Usually,
HEV causes a self-limiting hepatitis similar to hepati-
SUBJECTS AND METHODS
tis A [3]. Severe hepatitis has been reported, espe-
cially in pregnant women, mainly in the third Methods
trimester [5], in whom mortality can be up to 20%
Sera were tested using an EIA for the detection of anti-
[3]. No outbreaks have yet been described in devel-
HEV IgG (Abbott Laboratories, North Chicago, IL) as
oped areas of Europe [6,7] or the USA [8]. However,
previously described [11]. In brief, test and control
samples were incubated with polystyrene beads coated
Abbreviations: HEV, hepatitis E virus; ORF, open reading frame. with recombinant HEV proteins representing
Correspondence: Dr S. H. Hussaini, Division of Medicine, Level 7,
sequences of the open reading frames (ORF) 2 and 3 of
Clinical Science Building, St Jamess University Hospital, Leeds LS9 the Burmese isolate of HEV. After washing, the bound
7TF, UK. immunoglobulin was detected by using labelled goat

1997 Blackwell Science Ltd

52 S. H. Hussaini et al.
antibodies to human IgG. Reactive samples were then
tested by a modification of the assay, which substitutes
anti-IgM for the anti-IgG conjugate. The presence of
specific anti-HEV IgM was indicative of acute HEV
infection. The validation of the assay is described in
detail elsewhere [12]. However, in brief, both samples
described in this paper have been tested in the Genelabs
assay and confirmed positive.
Subjects
The subjects studied were two 23-year-old women,
pregnant, who had recently returned from a visit to the
Indian subcontinent.
RESULTS
Case 1
A 23-year-old lady, originating from Pakistan, was
admitted to hospital, 28 weeks pregnant, with a 2-day
history of jaundice and abdominal pain. She had
returned from Pakistan 5 weeks beforehand, having
stayed there for 2 months. On admission, she was not
encephalopathic, but was markedly jaundiced with no
stigmata of chronic liver disease. Her serum bilirubin
was raised at 126 mmol l1; she had a normal alanine
transaminase of 19 IU l1, a slightly raised alkaline
phosphatase of 339 IU l1 and a low serum albumin of
21 g l1. The patient spontaneously went into labour
and on the second day of admission gave birth to a
healthy baby. Thereafter she became progressively
drowsy and agitated, developing grade III hepatic
encephalopathy, approximately 36 h post delivery. She
was electively ventilated and received a 100 ml bolus of
20% mannitol when her left pupil transiently dilated.
The patient was transferred to a Liver Unit. On arrival,
emergency investigations revealed a prothrombin time
of 52 s (unsupported with fresh frozen plasma) and a
normal serum creatinine of 70 mol l1. Her serum
bilirubin was 323 mmol l1, alanine transaminase
399 IU l1 and serum albumin 28 g l1, when tested the
following morning, with a prothrombin time that had
fallen to below 50 s. Paracetamol was not detected in the
serum. She was haemodynamically stable, had a normal
intercranial pressure of 22 mm, normal gas exchange
with good urine output. Her platelet count was normal,
there being no evidence of intravascular haemolysis or
disseminated intravascular coagulation (DIC).
There were no surges of intercranial pressure or
episodes of sepsis during her stay in the intensive ther-
apy unit (ITU). Her prothrombin time progressively
improved, and she was extubated after 4 days in the
ITU. She was discharged home 8 days later.
Abdominal ultrasound of the liver and biliary tree
revealed no abnormality and doppler studies of the hep-
atic vein were normal. Her hepatitis A, B and C serol-
ogy were negative, as were serology for EpsteinBarr
virus, cytomegalovirus and adenovirus. However, she
was found positive for both hepatitis E IgG and IgM,
indicating acute infection.
Case 2
A Bangladeshi women, aged 23 years, returned from a
4-month visit to Bangladesh a week before admission
to hospital, with a 3-day history of jaundice. She was
31 weeks pregnant. Examination revealed marked
jaundice, with no stigmata of chronic liver disease. She
was not encephalopathic but had a deranged pro-
thrombin time of 62 s. Her alanine transaminase was
500 IU l1 and she had a serum bilirubin of
190 mmol l1. There was no thrombocytopenia, evi-
dence of intravascular haemolysis or DIC. Abdominal
ultrasound of the liver and biliary tree were normal. As
with the previous patient there were no serological
markers for hepatitis A, B and C or evidence of recent
infection with EpsteinBarr virus, cytomegalovirus and
adenovirus. She was, however, seropositive for hepati-
tis E IgG and IgM. Her clinical situation gradually
improved and she spontaneously delivered a healthy
baby girl 6 days after admission. Her prothrombin time
and alanine aminotransferase levels were normal by
the time of delivery. The patient was discharged home
4 days later.
DISCUSSION
We have described two cases of acute sporadic HEV
infection, presumably acquired abroad but presenting
in the UK one patient with hyperacute liver failure
[13], the other with severe hepatitis. In the first case,
the rapid progression from jaundice to encephalopathy
(less than 7 days) illustrates the speed of deterioration
in some patients. However, the rapid onset of jaundice
in patients with non-paracetamol induced acute liver
failure is a relatively good prognostic sign [14], as
shown in the first case. In this case the prompt treat-
1997 Blackwell Science Ltd, Journal of Viral Hepatitis, 4, 5154

ment of acute encephalopathy by ventilation and man-
nitol possibly prevented permanent neurological seque-
lae. Furthermore, the use of intercranial pressure moni-
toring allows the immediate treatment of surges in
intercranial pressure [15] characteristic of hyperacute
and acute liver failure [13]. The first patient had devel-
oped three of the OGrady criteria for liver transplanta-
tion in acute hepatic failure: non-A non-B aetiology,
prothrombin time of greater than 50 s and bilirubin
greater than 300 mmol l1 [14]. However, the raised
bilirubin was recorded at a time when the prothrombin
time was falling and thus this patient was not listed for
transplantation. There is no specific treatment for acute
liver failure. Nonetheless, intensive supportive medical
care in a specialized liver unit is critical for dealing with
the major complications of acute liver failure. These
include bacterial and fungal sepsis, haemodynamic
instability, renal and pulmonary impairment and coag-
ulopathy [16,17]. In patients with poor prognostic fac-
tors for recovery with conservative treatment, ortho-
topic liver transplantation may be offered [18].
The second case confirms that in most patients, the
infection, although causing severe hepatitis with
marked jaundice and coagulopathy, is often self limit-
ing and will spontaneously improve with conservative
therapy. The reasons for the high mortality associated
with HEV in pregnant women are not known, although
DIC has been noted in association with the disease [3].
A recent study from India indicated that death from
acute HEV infection is primarily a consequence of acute
hepatic failure [19]. However, if immediate, supportive
treatment can be given as in the two cases we describe,
the outcome should be favourable.
A possible differential diagnosis in both these cases
could have been acute fatty liver of pregnancy or the
Heamolysis, Elevated Liver Enzymes, Low Platelets
(HELLP) syndrome. However, these syndromes are
usually characterized by hypercoagulability and DIC
with evidence of intravascular haemolysis and throm-
bocytopenia in the case of the HELLP syndrome nei-
ther of which was found in the cases described.
Both pregnant women described here went into
spontaneous labour at 28 and 31 weeks respectively
and gave birth to normal babies. It is certainly possible
that delivery of the babies improved hepatic function,
as is the case in patients with acute fatty liver of preg-
nancy. Survival of these infants was probably a result
of good perinatal care. Foetal loss has been, in the past,
ascribed to maternal death or prematurity and surviv-
1997 Blackwell Science Ltd, Journal of Viral Hepatitis, 4, 5154
Hepatitis E in pregnancy 53
ing infants appear to have no chronic sequelae.
However, a recent paper suggests that HEV may be a
significant cause of perinatal morbidity and mortality
in women with mild or even subclinical infection [20]
and this needs further investigation.
A number of diagnostic tests for HEV have been
developed over recent years. Immune electron
microscopy using serum taken after acute HEV infec-
tion can be used to detect aggregates of viral particles in
stool samples [21]. In specimens obtained by liver
biopsy, the fluorescent antibody-blocking assay detects
HEV antigen present in hepatocytes [22]. The cloning
of the HEV [1] had led to the development of a number
of EIAs using recombinant expressed HEV antigens
[23,24], which are more convenient to use in clinical
practice. The assay we used was based on the detection
of antibodies to the ORF2 region, which contains
sequences thought to code for virus capsid proteins,
and the ORF3 region, which overlaps the ORF1 and
ORF2 regions of the viral RNA [1].
One of our cases had acute liver failure and was posi-
tive for IgM anti-HEV. The role of HEV in acute liver
failure is unclear. Sallie et al. [10], in a study from
London, found that eight of 42 patients with non-A
non-B acute liver failure had serum IgM anti-HEV anti-
bodies or HEV RNA detectable by the polymerase chain
reaction (PCR). However, there was poor correlation
between the EIA and PCR techniques. This finding was
interesting because only three of the eight patients had
a history of travel to areas where HEV was endemic. By
contrast, when we examined a group of 23 patients
with non-A non-B acute liver failure, none were found
to be positive for IgM anti-HEV [11]. This finding con-
firmed those of other groups studying the aetiology of
non-A non-B acute liver failure in France [7] and the
USA [8,25]. The lack of travel history to areas with
endemic HEV in our study [11], and in the French [7]
and American series [8,25], may explain the discrep-
ancy in the findings of HEV infection compared with
the London [10] study. Nonetheless, findings of HEV
infection in patients with acute hepatic failure and no
apparent risk [10] need to be corroborated.
In conclusion, we believe it is imperative to establish
the diagnosis of HEV in pregnant women with acute
hepatitis, as this group are at increased risk of acute
liver failure. Patients returning from endemic areas
and presenting with acute non-A non-B hepatitis
should be evaluated with high index of suspicion of
HEV infection. The diagnosis may be confirmed by EIAs
54 S. H. Hussaini et al.
using recombinant HEV antigens. Early recognition
and intensive treatment of acute liver failure caused by
HEV may reduce the high mortality reported in Asia.
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