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Liver International ISSN 1478-3223

REVIEW ARTICLE

Hepatitis E and pregnancy: understanding the pathogenesis


Udayakumar Navaneethan1, Mayar Al Mohajer1 and Mohamed T. Shata2
1 Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
2 Division of Digestive diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Keywords Abstract
fulminant liver failure hepatitis E hormonal Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale
immunology pregnancy epidemics of acute viral hepatitis, particularly in developing countries. In men and
non-pregnant women, the disease is usually self-limited and has a case-fatality rate
Correspondence
of less than o 0.1%. However, in pregnant women, particularly from certain
Dr Udayakumar Navaneethan, MD, geographical areas in India, HEV infection is more severe, often leading to
Department of Internal Medicine, University of fulminant hepatic failure and death in a significant proportion of patients. In
Cincinnati Medical Center, Cincinnati, OH, USA contrast, reports from Egypt, Europe and the USA have shown that the course and
Tel: 1513-558-6110 severity of viral hepatitis during pregnancy is not different from that in non-
Fax: 1513-558-1744 pregnant women. The reasons for this geographical difference are not clear. The
e-mail: navaneur@email.uc.edu
high mortality rate in pregnancy has been thought to be secondary to the
Received 28 May 2008
associated hormonal (oestrogen and progesterone) changes during pregnancy
Accepted 13 June 2008 and consequent immunological changes. These immunological changes include
downregulation of the p65 component of nuclear factor (NF-kB) with a
DOI:10.1111/j.1478-3231.2008.01840.x predominant T-helper type 2 (Th2) bias in the T-cell response along with host
susceptibility factors, mediated by human leucocyte antigen expression. Thus far,
researchers were unable to explain the high HEV morbidity in pregnancy, why it is
different from other hepatitis viruses such as hepatitis A with similar epidemiolo-
gical features and the reason behind the difference in HEV morbidity in pregnant
women in different geographical regions. The recent developments in under-
standing the immune response to HEV have encouraged us to review the possible
mechanisms for these differences. Further research in the immunology of HEV and
pregnancy is required to conquer this disease in the near future.

Enterically transmitted hepatitis E virus (HEV) infec- disease in France as in other developed countries (6).
tion is the most frequent cause of acute viral hepatitis Also, a recent study from France (7) has shown that
(AVH) in developing countries (1). The disease was post-transplant patients who are immunocompro-
first recognized in the Indian subcontinent in the mised progressed to chronic HEV infection.
1950s. Initially thought of as hepatitis A infection (2), In addition to this peculiar trait of progressing to
it took almost 30 years to recognize it as a different chronic hepatitis E in immunocompromised patients,
virus when the sera from persons during two water- HEV has an interesting course in pregnant women in
borne epidemics in India were negative for hepatitis A certain geographical regions of the world. Studies from
and B (3, 4). As research progressed in HEV infection, various developing countries have shown that the
the HEV genome was isolated and the enzyme-linked incidence of HEV infection in pregnancy is high and
immunosorbent (ELISA) and polymerase chain reac- a significant proportion of pregnant women can pro-
tion (PCR) assays to the HEV became available over gress to fulminant hepatitis, with a mortality rate
the last decade (5). varying from 30 to 100% (816). The mechanism of
In industrialized countries, hepatitis E is considered severe liver injury in pregnant women with hepatitis E
as an emerging disease of global importance and it has remains a mystery. In this review article, we have
been reported in a number of developed countries. A initially reviewed the normal hormonal and immuno-
recent survey of acute hepatitis E cases in France logical changes occurring during gestation and have
highlighted that hepatitis E is clearly an emerging later discussed in depth the interaction of hepatitis E

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Navaneethan et al. Hepatitis E and pregnancy

and pregnancy and the potential mechanisms respon- Hepatitis E can occur either in large epidemics (2, 4,
sible for its high mortality. 21) or in the form of sporadic cases. Although
We searched MEDLINE from 1980 to the present hepatitis E infection is endemic in Southeast and
using the Medical Subject Headings terms Hepatitis E, Central Asian countries, outbreaks have also been
Immunological changes and pregnancy, Hormones reported from several parts of the Middle East, Africa
and pregnancy, Hepatitis E and pregnancy, Hepatitis and Mexico.
E in pregnancy and mortality. Important clinical The outbreaks of hepatitis E are large and the overall
guidelines, large case series from centres of excellence, rates range from 1 to 15%, varying from 330% in
consensus conference and our own research develop- adults to 0.210% in children (4, 21, 26, 27). Children
ments form the basis of this review article. have a high rate of subclinical infection. In the US and
Before going into the interaction of HEV and Western Europe, o 1% of patients of AVH have
pregnancy, we have discussed some unique features of hepatitis E as the aetiology of their infection and it
hepatitis E infection that may play a role in patho- was thought to be associated with their travel to HEV-
genesis. endemic regions (28, 29). However, a recent paper
from France reporting that 90% of acute hepatitis E
Molecular virology of hepatitis E virus patients acquired it through the indigenous route by
contaminated water supplies and uncooked shellfish
Hepatitis E virus, a single-stranded RNA virus, was
may change this current perception of hepatitis E
first described in 1983 as spherical, 2730 nm virus-
epidemiology (6).
like particles. Analysis of its RNA helicase and RNA-
dependent RNA polymerase regions shows that HEV
forms a phylogenetically distinct group that was Clinical presentation of hepatitis E in
recently placed into a separate genus: Hepevirus (1). pregnancy
Characterization of HEV genomes from geographi-
The relationship between hepatitis E and pregnancy is
cally distinct locations has identified at least four
quite interesting. Hepatitis E has both a high incidence
major genotypes that may differ up to 20% at the
and a severe course in pregnant women in some
nucleotide level (17). While these are diverse in all
geographical regions of HEV-endemic countries, such
three open reading frame regions, they are serologi-
as Northern India (12, 13), while in other HEV-
cally indistinguishable and cross-reactive.
endemic countries, such as Egypt, it has been shown
Genotype 1 includes isolates from Asia, the Middle
to have a benign course with little or no morbidity
East and North Africa. Genotype 2 has been found in
(30). In a recent large prospective study from North-
Mexico and Nigeria. Genotype 3 was recovered from
ern India on the maternal and fetal outcomes of
swine in North America, Europe, Egypt, Asia and New
hepatitis E infection, close to 60% of viral hepatitis in
Zealand and from humans in North and South
pregnant women was attributed to hepatitis E infec-
America, Europe, Japan and China. Genotype 4 was
tion. Fulminant hepatic failure (FHF) was more com-
found in humans and swine in Asia (18).
mon among HEV-infected women (55%), who were at
Hepatitis E virus genotypes are also important as
a 2.7 times higher risk than non-HEV-infected women
they correlate with the severity of infection (19, 20).
(20%); maternal mortality was also higher secondary
Accumulating evidence suggests that genotypes 3 and
to FHF in the HEV-infected group (41%) vs. 7% in the
4 are less pathogenic in humans, while genotype 1 has
non-HEV group (13).
been shown to be more pathogenic. This explains the
Sporadic hepatitis E infection is also associated with
high severity of infection in India, where genotype 1 is
increased incidence and severity in pregnant women as
the most common subtype, in comparison with US,
reported by a study from India. Hepatitis E alone
where genotype 3 is the most common type seen.
contributed to approximately 50% of cases of AVH.
Fulminant liver failure was significantly higher in
Epidemiology pregnant women with HEV infection as opposed to
Hepatitis E virus is classically transmitted feco-orally, other causes of AVH (69.2 vs. 10%, P o 0.001). Also,
although person-to-person transmission has also been the prevalence and severity of HEV infection in
reported (21). HEV has been occasionally linked to pregnant women did not differ significantly in various
nosocomial spread (22). Vertical transmission from stages of gestation (16).
mother to infant is also known to occur (23). It is In contrast, in Egypt, where the prevalence of anti-
infrequently transmitted by transfusion of blood or HEV in rural communities is very high, severe HEV-
blood products (24, 25). caused AVH in pregnant women has not been

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reported. In one study of 2428 pregnant women, the genase, which inactivates and depletes tryptophan, an
anti-HEV prevalence was 84.3%. No patients with amino acid essential to T-cell function, and hence
AVH were reported (30). suppresses cell-mediated immunity at the fetuspla-
The reasons for the differences in the outcome of cental interface (37).
HEV in different geographical areas remain unclear Cytokines also contribute to immunological toler-
but could be the result of early childhood HEV ance as both the placenta and the trophoblasts secrete
exposures, producing long-lasting immunity and/or cytokines, including tumour growth factor b, interleu-
modifying subsequent responses to exposure to the kin (IL)-4 and IL-10, which inhibit cell-mediated
virus. Alternatively, the predominant HEV geno- immunity. In an attempt to understand the immunolo-
type(s) in Egypt could be less virulent than those in gical changes in pregnancy, Orsi et al. (38) measured
Asia (30, 31). The high risk of vertical transmission of serum cytokines in mouse models during different
HEV infection from mother to infant was investigated stages of pregnancy; levels of tumour necrosis factor a,
in a study of 469 pregnant women and a mother-to- IL-1b, IL-2, IL-6, IL-10, IL-12 (p40), IL-12 (p70) and
infant transmission of 100% was reported, although IL-17 (P o 0.05) were low during the initial phase of
there may have been a selection bias. Nonetheless, the pregnancy and increased markedly in late pregnancy
high transmission rate indicates the importance of and post-partum. Dudley et al. (39), in their murine
vertical transmission of HEV infection. A small per- model, also observed this, which reinforced the hypoth-
centage of the babies born to mothers with active esis that cytokine production during pregnancy favours
disease were either preterm or had anicteric hepatitis. antibody production over cytotoxic T-cell responses.
Two of the babies died within 48 h, while the remain- T-cells are markedly reduced during early pregnancy
ing 24 alive infants showed full recovery (32). up to the 20th week of gestation, leading to a reduced
Studies in animals to better understand the patho- level of immunity (4042). This modulation of cell-
genesis have also been non-contributory. In an animal mediated immunity occurs to allow fetal allograft
study that investigated the changes induced by HEV in retention, but it also alters the immune response
pregnant and non-pregnant primates (33), the course mounted against infections (43). The decrease in T-
of liver injury was similar in both groups. However, cell activity has been suggested to increase suscept-
this is not surprising, considering that HEV infection ibility to viral infections such as hepatitis, rubella,
in primates leads only to a milder form of liver injury. herpes and human papilloma virus and also to infec-
The severe liver injury because of HEV infection tions like malaria during pregnancy (44), but it also
during pregnancy may be related to one of several explains why cell-mediated immune diseases like
possible host factors, such as differences in immune rheumatoid arthritis improve during gestation.
and hormonal factors occurring during pregnancy and While some studies have argued that there is no
genetic and environmental factors, with its occurrence alteration in the number of total T-lymphocytes or in
in certain developing countries. We have explored all CD41 lymphocytes in pregnancy (45, 46), others have
these issues in this article. suggested an initial decrease until 20 weeks to sustain
the fetus during the implantation phase and then an
increase or normalization later during pregnancy or
Immunological changes during pregnancy the post-partum period (4753). The apparent re-
During pregnancy, the maternal immune system is sponse to pregnancy of CD8 lymphocytes, although
clearly altered to tolerate a genetically different fetus less well studied, is either a slight decrease or stability
(34, 35). The outer layer of the placenta is made of throughout gestation (46, 5052, 54, 55).
trophoblasts, which forms the interface between the To summarize, the immunological changes during
maternal and the fetal circulations. Trophoblasts do pregnancy promote the maintenance of the antigenic
not express major histocompatibility complex (MHC) fetus in the maternal environment by suppression of
class proteins and are hence resistant to T-cell- T-cell-mediated immunity. There is a clear shift in the
mediated injury, which is a protective phenomenon T-helper type 1 (Th1):Th2 cell paradigm during
to sustain the fetus. However, the natural killer (NK) pregnancy, with a definite skew towards Th2 cells.
cells do not require MHC proteins and the tropho- The levels of most cytokines are depressed particularly
blasts are protected against the NK cells as they express during the initial 20 weeks of pregnancy, which is an
a unique human leucocyte antigen (HLA) molecule important phase to sustain the fetus. Whether this
called HLA-G, which binds to NK receptors CD 16 and suppressed immune system translates into an in-
CD 56 and inactivates them (36). The placenta also creased risk of infections during pregnancy is still not
expresses an enzyme called indoleamine 2, 3-dioxy- clear with the available data.

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Hormonal factors in pregnancy tion. Mice lacking the p65 component of NF-kB
Hormonal factors during pregnancy may also play a showed evidence of widespread apoptosis, which led
significant role in altering immune regulation or viral to recent attempts to study this phenomenon in
replication (56, 57). Levels of progesterone, oestrogen humans. Prusty et al. (68) studied the changes in NF-
and human chorionic gonadotropin (HCG) increase kB activity using electrophoretic assays of the p50 and
with pregnancy. In animal studies, these hormones p65 components in pregnant and non-pregnant pa-
have been shown to have a clear suppressive effect on tients with FHF because of hepatitis B, C and E. Their
the cell-mediated immunity. HCG has been shown to results replicated the results in animal experiments
inhibit cell-mediated immunity in guinea-pigs (58), and they found that the activity of the p65 component
while oestrogen causes shrinkage of thymus and of NF-kB was diminished in both the peripheral blood
depletes the CD4 and CD8 populations in mice (59, mononuclear cells and the post-mortem liver biopsy
60) and progesterone produces involution of the specimens in pregnant patients with fulminant liver
thymus and blocks T-cell development and inhibits failure. There was a higher than normal level of p50
Th1 cell and promotes Th2 cell development (61). expression, but there was a near-complete absence or a
Progesterone has specifically been shown to impair the minimal expression of p65. The absence of p65 from
transition of pro-T-cells to early pre-T-cells in mice the NFkB complex produced fulminant liver damage
models (61). The expression of thymic stromal pro- (68). Their results established that the absence of p65
gesterone receptors is required to produce involution was probably responsible for severe liver damage in
of the thymus and they play a greater role than pregnant FHF patients. This hypothesis has also been
oestrogen in producing thymic involution (60, 61). further supported in other viruses, where recent
Despite these changes, the numbers of peripheral T- studies have shown decreased expression of p65 caus-
and B-cells are unchanged as the half-life of peripheral ing liver fibrosis and liver damage in patients with
lymphocytes is higher. Studies have also shown that HCV-induced chronic liver disease (69). The expres-
there is also a decrease in bone marrow B-cell produc- sion of NF-kB, physiologically downregulated during
tion, mainly pre-B and immature (fractions BD) pregnancy, also plays an important role in sustaining
bone marrow B-cells, in pregnant mice because of the the fetus during pregnancy (70).
increase in oestrogen and progesterone levels during Jilani et al. found that HEV-infected pregnant
pregnancy (62). women with FHF had lower CD4 counts and higher
In addition, there are evidences indicating that CD8 counts. They also observed that the levels of
steroid hormones may influence viral replication (63, oestrogen, progesterone and b-HCG were significantly
64). For example, hormonal enhancement of cytome- higher in the above-mentioned group when compared
galovirus (CMV) replication may be a possible me- with HEV-negative patients or control healthy preg-
chanism responsible for the increased incidence of nant females (71). Although the levels of hormones
CMV infection observed during human pregnancy were physiologically high in the normal control popu-
(63). There are also reports of increased predisposition lation, patients with HEV infection seemed to have
to viral infection in certain high-oestrogen states (64). significantly higher levels than controls, which prob-
ably explains the direct interaction of HEV with the
immune system.
Mechanisms responsible for the high Pal et al. (72) studied the cellular immune response
morbidity of hepatitis E in pregnancy in both pregnant and non-pregnant women with acute
As discussed previously, pregnancy is associated with hepatitis E and the control population and found that
high levels of steroid hormones. These steroid hor- pregnant women with HEV had generalized immune
mones may promote viral replication. It also directly suppression characterized by a decrease in lymphocyte
inhibits hepatic cells, which may predispose to hepatic response to phytohaemagglutinin (PHA) with a pre-
dysfunction/failure when exposed to infectious patho- dominant Th2 bias as compared with non-pregnant
gens (65). Steroid hormones are immunosuppressive women with hepatitis E and normal healthy controls.
(66) and mediate lymphocyte apoptosis through NF- This challenged the previously existing hypothesis that
kB. NF-kB is a eukaryotic dimeric transcription factor normal pregnancy is associated with systemic immune
that has multiple cellular effects, including liver devel- suppression with an increased risk of infections
opment and regeneration and their effects on the (7376). This study was important from a number of
immune response (67). Animal experiments in mice perspectives. The thought that normal pregnancy is an
studying the p65 component of NF-kB have shown immunosuppressed state is challenged because normal
their primary role in liver development and regenera- healthy pregnant women did not demonstrate a

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decreased response to PHA. Also, non-pregnant pa- shift (78) may have been responsible for the different
tients with HEV did not show any defective PHA geographical morbidity in pregnant women in South-
response, probably indicating that HEV by itself does ern India and Egypt. If this hypothesis holds true, it
not produce the immunological changes and needs opens up the intriguing possibility of the exploration
pregnancy as a physiological state to produce the of the genotype in pregnancy.
above-mentioned changes. The Th2 bias observed in In addition to the above-mentioned factors, Khuroo
the present study was specific to HEV infection during et al. (79) suggested that infection of the fetus with
pregnancy. It may be just that the Th2 bias is very HEV may be responsible for the increased severity of
much prominent in HEV infection as compared with the disease in the mother; Variations in the MHC,
normal pregnancy. The mechanism by which Th2 bias which mediate antigen presentation, may also explain
may lead to a more severe disease course in pregnant some of the differences in the mortality in different
women with hepatitis E needs further investigation. geographical areas in women infected with HEV (80,
With this Th2 bias, it was suggested that decreased 81). Recently, an editorial commented that HEV-
cellular-mediated immunity is considered a major infected pregnant women as a group may be more
cause of death in Asian pregnant women with fulmi- commonly taking herbal medications, which could
nant hepatitis caused by HEV infection. explain the high mortality in certain geographical
If all the hypotheses of immunological and hormo- regions (82). However, in our centre back home, where
nal factors interacting with the genetic susceptibility in herbal medication use is very common, we have
Asian women hold true, we should expect a high observed that the mortality rate is low (77, 83). At the
mortality in pregnancy from all HEV-endemic regions. same time, we observed that the use of herbal medica-
But this is not always true. Two studies, from Chennai, tions was an independent predictor for poor prognosis
Southern India, and Egypt, despite indicating the high in patients with acute liver failure because of other
prevalence of hepatitis E infection in pregnancy, also aetiologies (83).
had very interesting observations. The mortality rate Also, a recent study of post-transplant patients from
of hepatitis E infection was very low (3.4%) (77) and France, reporting the increased risk of acute hepatitis E
absent (30), respectively, as against 30100% reported progressing to chronicity, has reiterated the impor-
in various studies in HEV-endemic regions (816). tance of an immune response to protect against
Also, most of the HEV-infected pregnant women had infection (7). However, as observed, all these patients
normal-term deliveries. These studies may underline were post-transplant and patients who progressed to
the importance of viral genotypes in the pathogenesis chronic hepatitis had significantly lower levels of CD3
and severity of HEV infection. The results of various and CD4 cells, highlighting the importance particu-
studies from endemic regions have been summarized larly of T-cell-mediated immunity for pathogen clear-
in Table 1. We hypothesized that the difference in the ance. This difference in presentation is really
genotype or subtypes of the HEV infection could be interesting. The progression to fulminant liver failure
the answer (77). Genotype 1 is the most common in pregnant women could be because of immunologi-
subtype causing HEV infection in India, while geno- cal injury, while chronic hepatitis could be mediated
type 3 predominates in the US. Genotype 1 has been by failure to inhibit viral replication, given that these
further classified into four subtypes and most of them patients were immunosuppressed and immunological
have been grouped into genotype 1A. A subgenotype injury was absent. Further research is required to

Table 1. Studies on hepatitis E infection and pregnancy


Prevalence of hepatitis Prevalence of fulminant Mortality
Study Patients (n) E virus infection (%) liver failure (%) rate (%)
Jaiswal et al. (15) (North India) 127 58 58 45
Singh et al. (14) (North India) 60 37 64 64
Khuroo et al. (16) (North India) 76 86 69 55
Beniwal et al. (8) (North India) 97 47.4 75 39.1
Tsega et al. (10) (Ethiopia) 32 59 42
Kumar et al. (12) (North India) 65 45 32 73
Patra et al. (13) (North India) 220 60 55 41
Stoszek SK et al. (30) (Egypt) 2428 84.3 0 0
Rasheeda et al. (77) (South India) 115 75 3.4 3.4
Studies with low morbidity and mortality in pregnancy.

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Navaneethan et al. Hepatitis E and pregnancy

understand the implications of immunology and tis E infection. However, in a retrospective study from
hepatitis E infection. India, Banait et al. (85) studied 42 patients with HEV-
Thus, there is a complex interaction among viral, induced liver failure; there was no difference in mater-
host, immunological and hormonal factors, producing nal mortality in pregnant women who delivered and
a paradigm of severe liver damage in pregnancy, those who did not, questioning the role of therapeutic
probably immunologically, which is summarized in termination. The literature at present is not supportive
Figure. 1. The probable hypothesis of pathogenesis of of the fact that delivery of the baby may decrease
hepatitis E depending on the host immune function is maternal mortality. However, this was a small retro-
summarized in Figure. 2. spective study and must not discourage physicians
from pursuing that option, considering that HEV
infection also produces immunological changes in the
Management fetus. Studies have also explored the role of preventing
The mechanism of liver injury in hepatitis E is not HEV in high-risk endemic countries, given the high
clear and all the hypotheses put forth have not yet been maternal and fetal morbidity and mortality. Arankalle
proved conclusively. In this situation of uncertainty, et al. (86) used an Indian-made preparation of im-
the management of HEV infection-induced liver fail- mune serum globulin based on locally prevalent
ure assumes more importance than ever before. All the genotypes in preventing hepatitis E among pregnant
studies have shown that pregnant women have a women during an epidemic. Patients who received
differential immune response that triggers fulminant immune globulin had a lower frequency of HEV
liver failure. Hence, the logical treatment should be to infection than in the control population (18.1 vs.
deliver the fetus as soon as possible. Unfortunately, 33.9%). However, that study was limited by the small
very few such studies have been undertaken in this number of patients and did not have sufficient power
field. Therapeutic termination of pregnancy, which to be conclusive. At present, although there is no
has been proven to be beneficial in pregnancy-specific consensus to treat patients with HEV infection in
disorders like HELLP syndrome and acute fatty liver of pregnancy, early delivery of the fetus, if possible, to
pregnancy (84), has not been fully explored in hepati- prevent maternal mortality should be attempted.

Suppression of CD4 cells Immunological Factors


Hormonal Factors
Th2 predominant response
Increase oestrogen and progesterone
Low CD4, High CD8

Host Factors
Increased viral replication HLA-G susceptibility
PREGNANCY

Malnutrition, Folate
HEPATITIS E VIRUS deficiency

? Viral factors-Differences
in genotypes
Inhibition of p65 component Direct Immunological damage/
Of NF-KB Virus mediated

Fulminant liver failure


Certain endemic regions ? Delivery of fetus
High morbidity

Death Survival

Fig. 1. Pathogenesis of hepatitis E virus in pregnancy.

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Hepatitis E and pregnancy Navaneethan et al.

HEPATITIS E VIRUS

Immune dysregulation, Altered T cell ratio


T cell and B cell dysfunction Decreased CD4
Increased CD8
Viral Factors

Immunocompromised patients
Post transplant Pregnancy-? Immunological mediated
? Direct viral mediated injury injury

? Genotype 1 Host susceptibility


? Genotype 3
? Sub genotype shift factors

Chronic hepatitis E infection


Acute liver failure (20%)

Fig. 2. Probable hypotheses for the variable pathogenesis of hepatitis E virus.

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