Book on hepatitis from Page 46 Lee 59

Book on hepatitis from Page 46 Lee 59

46  Hepatology 2012
Organ transplantation
Transplant recipients who receive organs from HCV-positive donors have a high
risk of acquiring HCV infection. Transmission rates in different cohorts vary from
30 to 80% (Pereira 1991, Roth 1994). Therefore, most transplant organisations have
developed strategies for screening and selective utilization of organs from anti-HCV
positive donors.
Sexual or household contact
Usual household contacts do not pose a risk of HCV transmission.
The efficiency of HCV transmission by sexual contact is very low. However,
there is no doubt that sexual transmission of hepatitis C is possible.
The exact risk of HCV transmission in monogamous heterosexual relationships
has been difficult to determine. It appears that the risk in long-term partnerships is
very low. In prospective cohorts of monogamous, heterosexual couples, there was a
long-term transmission risk of 0.01% or lower (Vandelli 2004). Factors that may
increase the risk of HCV infection include greater numbers of sex partners, history
of sexually transmitted diseases, and not using a condom. Whether underlying HIV
infection increases the risk of heterosexual HCV transmission to an uninfected
partner is unclear. Very often it is difficult to rule out the possibility that
transmission results from risk factors other than sexual exposure.
Outbreaks of cases of acute hepatitis C in several cities in Europe and the United
States among men who have sex with men (MSM) have focused attention on sexual
transmission of HCV (Boesecke 2011). There is clear evidence unprotected sex can
account for the transmission of HCV. Unprotected anal sex, fisting, having many
sex partners in a short time period, a concomitant sexually transmitted disease
including HIV and use of recreational drugs were identified as risk factors (Danta
2007, Schmidt 2011). It appears that mucosal damage is a prerequisite for HCV
transmission. According to these observations, the seroprevalence of HCV in MSM
ranges from about 4 to 8%, which is higher than the HCV prevalence reported for
general European populations.
Patients with acute or chronic HCV infection should be advised that transmission
to sexual contacts is a possibility, although the risk is extremely low in heterosexual
relationships. It is likely that the use of condoms will lower the risk of sexual
transmission further. However, in most countries there are no firm
recommendations to use barrier precautions in stable monogamous sexual
partnerships. The transmission risk in MSM is considerably higher so that – in
conjunction with the risk of other sexually transmitted diseases – safer sex practices
are advised for this group.
Perinatal transmission
The risk of perinatal transmission of HCV in HCV RNA-positive mothers is
estimated to be 5% or less (Ohto 1994). In mothers coinfected with HIV this risk
correlates with immunosuppression and has been described in up to 20%. Today,
there are no specific recommendations for prevention of perinatal transmission
(Pembrey 2005). Cesarean section has not been shown to reduce the transmission
risk. There is no evidence that breastfeeding is a risk for infection among infants
born to HCV-infected women. Early diagnosis of infection in newborns requires
Hepatitis C  47
HCV RNA testing since anti-HCV antibodies are passively transferred from the
mother.
Hemodialysis
Patients who participate in chronic hemodialysis programs are at increased risk for
hepatitis C. The prevalence of HCV antibodies in such patients reaches 15%,
although it has declined in recent years (Fissell 2004). A number of risk factors have
been identified for HCV infection among dialysis patients. These include blood
transfusions, duration of hemodialysis, prevalence of HCV infection in the dialysis
unit, and type of dialysis. The risk is higher with in-hospital hemodialysis as
opposed to peritoneal dialysis. The best strategy to prevent hemodialysis-associated
HCV transmission is subject to debate.
Other rare transmission routes
Rare sources of percutaneous transmission of HCV are contaminated equipment
used during medical procedures, procedures involved in traditional medicine (e.g.,
scarification, cupping), tattooing, and body piercing (Haley 2001). All these routes
bear the potential of transmitting HCV. However, in most instances it is not clear if
the risk is due to the procedure itself, or whether there are possible contacts with
persons involved who are HCV-positive. In addition, transmission via these routes
is so rare that persons with exposure are not at increased risk for acquiring hepatitis
C.
Needlestick injury
There is some risk of HCV transmission for health care workers after unintentional
needlestick injury or exposure to other sharp objects. The incidence of
seroconversion after exposure to an HCV-positive source is generally estimated to
be less than 2% (MMWR 2001). However, data are divergent and figures ranging
from 0 to 10% can be found (Mitsui 1992). Exposure of HCV to intact skin has not
been associated with HCV transmission.
Clinical manifestations
The spectrum of clinical manifestations of HCV infection varies in acute versus
chronic disease. Acute infection with HCV is most often asymptomatic (Vogel
2009) and leads to chronic infection in about 80% of cases. The manifestations of
chronic HCV range from an asymptomatic state to cirrhosis and hepatocellular
carcinoma. HCV infection usually is slowly progressive. Thus, it may not result in
clinically apparent liver disease in many patients if the infection is acquired later in
life. Approximately 20-30% of chronically infected individuals develop cirrhosis
over a 20-30 year period of time.
Acute hepatitis
After inoculation of HCV, there is a variable incubation period. HCV RNA in blood
(or liver) can be detected by PCR within several days to eight weeks.
Aminotransferases become elevated approximately 6-12 weeks after exposure
(range 1-26 weeks). The elevation of aminotransferases varies considerably among
individuals, but tends to be more than 10-30 times the upper limit of normal
48  Hepatology 2012
(typically around 800 U/l). HCV antibodies can be found for the first time around 8
weeks after exposure although in some patients it may take several months before
HCV antibodies can be detected by ELISA testing.
However, the majority of newly-infected patients will be asymptomatic and have
a clinically non-apparent or mild course. Jaundice as a clinical feature of acute
hepatitis C will be present in less than 25% of infected patients. Therefore, acute
hepatitis C will not be noticed in most patients (Vogel 2009). Periodic screening for
infection may be warranted in certain groups of patients who are at high risk for
infection, e.g., homosexually-active patients with HIV infection.
Other symptoms that may occur are similar to those in other forms of acute viral
hepatitis, including malaise, nausea, and right upper quadrant pain. In patients who
experience such symptoms of acute hepatitis, the illness typically lasts for 2-12
weeks. Along with clinical resolution of symptoms, aminotransferases levels will
normalize in about 40% of patients. Loss of HCV RNA, which indicates cure from
hepatitis C, occurs in fewer than 20% of patients regardless of normalisation of
aminotransferases.
Fulminant hepatic failure due to acute HCV infection is very rare. It may be more
common in patients with underlying chronic hepatitis B virus infection (Chu 1999).
Chronic hepatitis C
The risk of chronic HCV infection is high. 80-100% of patients remain HCV RNA
positive after acute hepatitis C (Alter 1999, Vogel 2009). Most of these will have
persistently elevated liver enzymes in further follow-up. By definition, hepatitis C is
regarded to be chronic after persistence of more than six months. Once chronic
infection is established, there is a very low rate of spontaneous clearance.
It is unclear why infection with HCV results in chronic infection in most cases.
Genetic diversity of the virus and its tendency toward rapid mutation may allow
HCV to constantly escape immune recognition. Host factors may also be involved
in the ability to spontaneously clear the virus. Factors that have been associated with
successful HCV clearance are HCV-specific CD4 T cell responses, high titers of
neutralising antibodies against HCV structural proteins, IL28B gene polymorphisms
and specific HLA-DRB1 and -DQB1 alleles (Lauer 2001, Thomas 2009, Rauch
2010). Infection with HCV during childhood appears to be associated with a lower
risk of chronic infection, approximately 50-60% (Vogt 1999). Finally, there seem to
be ethnic differences, with lower risk of chronicity in certain populations.
Most patients with chronic infection are asymptomatic or have only mild
nonspecific symptoms as long as cirrhosis is not present (Merican 1993, Lauer
2001). The most frequent complaint is fatigue. Less common manifestations are
nausea, weakness, myalgia, arthralgia, and weight loss. HCV infection has also been
associated with cognitive impairment. All these symptoms are non-specific and do
not reflect disease activity or severity (Merican 1993). Very often symptoms may be
caused by underlying diseases (e.g., depression), and it can be difficult to
distinguish between different diseases. Fatigue as the most common symptom may
be present in many other situations (including healthy control groups within clinical
studies). Hepatitis C is rarely incapacitating.
Aminotransferase levels can vary considerably over the natural history of chronic
hepatitis C. Most patients have only slight elevations of transaminases. Up to one
third of patients have a normal serum ALT (Martinot-Peignoux 2001, Puoti 2002).
Hepatitis C  49
About 25% of patients have a serum ALT concentration of more than twice normal,
but usually less than 5 times above the upper limit of normal. Elevations of 10 times
the upper limit of normal are very seldomly seen.
There is a poor correlation between concentrations of aminotransferases and liver
histology. Even patients with normal serum ALT show histologic evidence of
chronic inflammation in the majority of cases (Mathurin 1998). The degree of injury
is typically minimal or mild in these patients. Accordingly, normalisation of
aminotransferases after interferon therapy does not necessarily reflect histologic
improvement.
Extrahepatic manifestations
Around 30 to 40% of patients with chronic hepatitis C have an extrahepatic
manifestation of HCV (Zignego 2008). There is a wide variety of extrahepatic
manifestations described as being associated with HCV:
−  Hematologic manifestations (essential mixed cryoglobulinemia, lymphoma)
−  Autoimmune disorders (thyroiditis, presence of various autoantibodies)
−  Renal disease (membranoproliferative glomerulonephritis)
−  Dermatologic disease (porphyria cutanea tarda, lichen planus)
−  Diabetes mellitus
For further details refer to Chapter 16.
Natural history
The risk of developing cirrhosis within 20 years is estimated to be around 10 to
20%, with some studies showing estimates up to 50% (Poynard 1997, Wiese 2000,
Sangiovanni 2006, de Ledinghen 2007). Due to the long course of hepatitis C the
exact risk is very difficult to determine, and figures are divergent for different
studies and populations. In fact, chronic hepatitis C is not necessarily progressive in
all affected patients. In several cohorts it has been shown that a substantial number
of patients will not develop cirrhosis over a given time. It is estimated that about
30% of patients will not develop cirrhosis for at least 50 years (Poynard 1997).
Therefore, studies with short observation periods sometimes fail to show an
increase in mortality. In addition, survival is generally not impaired until cirrhosis
has developed. On the other hand, there is no doubt that patients with chronic
hepatitis C have a high risk of cirrhosis, decompensation, and hepatocellular
carcinoma in long-term follow-up. For example, in a cohort of patients with post-transfusion hepatitis C evaluated more than 20 years after transfusion 23% had
chronic active hepatitis, 51% cirrhosis, and 5% hepatocellular carcinoma (Tong
1995). It is not completely understood why there are such differences in disease
progression. An influence of host and viral factors has to be assumed.
Cirrhosis and hepatic decompensation
Complications of hepatitis C occur almost exclusively in patients who have
developed cirrhosis. Interestingly, non-liver related mortality is higher in cirrhotic
patients as well. However, cirrhosis may be very difficult to diagnose clinically, as
most cirrhotic patients will be asymptomatic as long as hepatic decompensation
does not occur. Findings that can be associated with cirrhosis are hepatomegaly
50  Hepatology 2012
and/or splenomegaly on physical examination, elevated serum bilirubin
concentration,  hyperalbuminemia, or low platelets. Other clinical findings
associated with chronic liver disease may be found such as spider angiomata, caput
medusae, palmar erythema, testicular atrophy, or gynaecomastia. Most of these
findings are found in less than half of cirrhotic patients, and therefore none is
sufficient to establish a diagnosis of cirrhosis.
Hepatic decompensation can occur in several forms. Most common is ascites,
followed by variceal bleeding, encephalopathy and jaundice. As mentioned earlier,
hepatic decompensation will develop only in cirrhotic patients. However, not all
patients with cirrhosis actually show signs of decompensation over time. The risk
for decompensation is estimated to be close to 5% per year in cirrhotics (Poynard
1997). Once decompensation has developed the 5-year survival rate is roughly 50%
(Planas 2004). For this group of patients liver transplantation is the only effective
therapy.
Similar to decompensation, hepatocellular carcinoma (HCC) develops solely in
patients with cirrhosis (in contrast to chronic hepatitis B). The risk for HCC has
been estimated to be less than 3% per year once cirrhosis has developed (Di
Bisceglie 1997, Fattovich 1997). However, HCV-associated HCC has significant
impact on survival (see Chapter 21).
Elevated concentrations of α-fetoprotein (AFP) do not necessarily indicate HCC.
AFP may be mildly elevated in chronic HCV infection (i.e., 10 to 100 ng/mL).
Levels above 400 ng/mL as well as a continuous rise in AFP over time are
suggestive of HCC.
Disease progression
Chronic hepatitis C has different courses among individuals. It is not completely
understood why there are differences in disease progression. Several factors have
been identified that may be associated with such differences. However, other factors
not yet identified may also be important.
Age and gender: Acquisition of HCV infection after the age of 40 to 55 may be
associated with a more rapid progression of liver injury, as well as male gender
(Svirtlih 2007). On the contrary, children appear to have a relatively low risk of
disease progression (Child 1964). In one cohort, for example, only 1 of 37 patients
with HCV RNA in serum had elevated levels of serum aminotransferases, and only
3 of 17 (18%) who had liver biopsies approximately 20 years after exposure had
histologic signs of progressive liver disease.
Ethnic background: Disease progression appears to be slower and changes in
liver histology less severe in African-Americans (Sterling 2004).
HCV-specific cellular immune response: The severity of liver injury is
influenced by the cellular immune response to HCV-specific targets. Inflammatory
responses are regulated by complex mechanisms and probably depend on genetic
determinants such as HLA expression (Hraber 2007). Whether this determines
progression of liver disease is not clear.
Alcohol intake: Alcohol increases HCV replication, enhances the progression of
chronic HCV, and accelerates liver injury (Gitto 2009). Even moderate amounts of
alcohol appear to increase the risk of fibrosis. Accordingly, in alcoholic patients
with cirrhosis and liver failure a high prevalence of anti-HCV antibodies has been
Hepatitis C  51
described. Alcohol intake should be avoided in all patients with chronic hepatitis C.
There is no clear amount of safe alcohol intake.
Daily use of marijuana: Daily use of marijuana has been associated with more
rapid fibrosis progression, possibly through stimulation of endogenous hepatic
cannabinoid receptors.
Other host factors: Genetic polymorphisms of certain genes might influence the
fibrosis progression rate (Jonsson 2008). For example, transforming growth factor
B1 (TGF B1) phenotype or PNPLA3 (adiponutrin) are correlated with fibrosis stage
(Zimmer 2011). Patients with moderate to severe steatosis are at higher risk for
developing hepatic fibrosis.
Viral coinfection: Progression of hepatitis C clearly is accelerated in HIV-infected patients (see section on coinfection). Acute hepatitis B in a patient with
chronic hepatitis C may be more severe. Chronic hepatitis B may be associated with
decreased HCV replication as opposed to HCV monoinfected patients, although
HCV usually predominates. Nevertheless, liver damage is usually worse and
progression faster in patients with dual HBV/HCV infections. Around one third of
patients coinfected with HBV and HCV lack markers of HBV infection (i.e.,
HBsAg) although HBV DNA is detectable.
Geography and environmental factors: There are some obvious geographic
differences (Lim 2008). For example, hepatocellular carcinoma is observed more
often in Japan than in the United States. The reason for this is not clear.
Use of steroids: It is well known that use of steroids increases the HCV viral
load, while the effect on aminotransferases is variable. They tend to decrease in
most patients, although increases in transaminases and bilirubin have also been
described. Reducing dosage of corticosteroids returns HCV viral load to baseline.
However, the clinical consequences of corticosteroid use are largely unknown. It
seems to  be reasonable to assume that short-term use of corticosteroids is not
associated with significant changes in long-term prognosis.
Viral factors: The influence of viral factors on disease progression is unclear.
Overall, there seems to be no significant role of different genotypes and
quasispecies on fibrosis progression or outcome. However, coinfection with several
genotypes may have a worse outcome as compared to monoinfection.
It is very difficult to predict the individual course of hepatitis C due to the many
factors influencing disease progression. Today, assessment of liver fibrosis by non-invasive techniques such as transient elastography, AFRI or by liver biopsy is the
best predictor of disease progression (Gebo 2002). The grade of inflammation and
stage of fibrosis are useful in predicting further clinical course. In patients with
severe inflammation or bridging fibrosis virtually all patients will develop cirrhosis
within ten years. In contrast, patients with mild inflammation and no fibrosis have
an annual progression risk to cirrhosis of around 1%.
Several predictive models of disease progression that include clinical parameters
(e.g., hepatic decompensation) and laboratory parameters (e.g., bilirubin, INR) have
been evaluated, but none of these models is routinely used in the clinic at present. In
patients with cirrhosis, the MELD score (Model for End-Stage Liver Disease) and
the Child score (Table 1) are used to stage disease and to describe the prognosis (see
Chapters 22 & 23). The MELD Score is used especially to estimate relative disease
severity and likely survival of patients awaiting liver transplant. It is calculated as:
MELD Score = 10 x ((0.957 x ln(Creatinine)) + (0.378 x ln(Bilirubin)) + (1.12 x
52  Hepatology 2012
ln(INR))) + 6.43. An online calculator and further information can be found at the
website of The United Network for Organ Sharing (UNOS) (http://www.unos.org).
Table 1. Child-Pugh classification of severity of liver disease (Child 1964).*
Points assigned
1  2  3
Ascites  Absent  Slight  Moderate
Bilirubin, mg/dL  <2  2-3  >3
Albumin, g/dL  >3.5  2.8-3.5  <2.8
Prothrombin time  
Seconds over control  <4  4-6  >6
INR  <1.7  1.7-2.3  >2.3
Encephalopathy  None  Grade 1-2  Grade 3-4
* A total score of 5-6 is considered stage A (well-compensated disease); 7-9 is stage B
(significant functional compromise); and 10-15 is stage C (decompensated disease). These
grades correlate with one- and two-year patient survival (stage A: 100 and 85 percent; stage B:
80 and 60 percent; stage C: 45 and 35 percent).
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Hepatitis E: an underestimated problem?  55
4.  Hepatitis E: an underestimated problem?
Sven Pischke and Heiner Wedemeyer
Introduction
Hepatitis E is an inflammatory liver disease caused by the hepatitis E virus (HEV),
which is endemic in many tropical countries. Hepatitis E has been considered to be
a travel-associated, acute, self-limiting liver disease that only causes fulminant
hepatic failure in specific, high-risk groups. It has recently been estimated that HEV
infection causes approximately 70,000 deaths each year worldwide (Rein 2011). In
recent years sporadic cases of HEV infections have emerged also in industrialized
countries, mostly caused by HEV genotype 3, for which zoonotic transmission has
been described (Pischke 2010b).
In immunocompetent individuals infection with HEV usually leads to a clinically
silent seroconversion or to an acute self-limited inflammation of the liver. In
pregnant women and patients with pre-existing chronic liver diseases cases of
fulminant liver failure by HEV infection are reported (Pischke 2010b).
Moreover, cases of chronic HEV infection associated with progressive liver
disease have been described in several cohorts of immunocompromised individuals.
In this context, diagnosis of HEV infection should rely on detection of HEV RNA,
as testing for HEV-specific antibodies may lack sensitivity (Pischke 2010c).
Therapeutic options for chronic hepatitis E include reduction of
immunosuppressive medication (Kamar 2011a), treatment with  α-interferon
(Haagsma 2010, Kamar 2010a) or therapy with ribavirin (Kamar 2010b, Mallet
2010).
Recently, results of a large Phase III study were presented investigating a novel
recombinant HEV vaccine in China. The vaccine had an efficacy to prevent acute
symptomatic hepatitis E of >90% (Zhu 2010). It is unknown yet if and when this
vaccine might become available for other countries.
HEV: genetic characteristics of the virus
The hepatitis E virus is a non-enveloped, single-stranded RNA virus classified into
the family of Hepeviridae and its own genus Hepevirus (Pischke and Wedemeyer
2010). There are 5 known genotypes. The HEV genome includes two short non-coding regions surrounding three open reading frames (ORF1 to 3). These ORFs
contain the genetic information for various proteins that are necessary for capsid
56  Hepatology 2012
formation, virus replication and infectivity of HEV. Various HEV isolates have
been differentiated by phylogenetic analysis based on a hypervariable region within
ORF1 (Meng 1999). Four of five HEV genotypes are able to infect humans, while
genotype 5, called “avian HEV”, has only been detected in birds.
HEV genotype 1 is responsible for endemic and epidemic infections by HEV in
Asia, while genotype 2 is endemic in Africa and Mexico (Figure 1). These
genotypes are usually transmitted orally-faecally by contaminated drinking water
under conditions of poor sanitation. There is no known animal reservoir for these
genotypes (Pischke 2010b).
HEV genotype 3 can be found in humans and animals in Europe, the US and Asia
(Pischke 2010b). For this genotype zoonotic transmission, foodborne or by contact
with infected animals has been described. HEV genotype 3 has been identified in
pigs, wild boars, shellfish, deer, oysters, cats, rats and various rodents (Pischke
2010b). Genotype 4 has also been detected in both humans and pigs in Asia (Geng
2009) and Europe (Hakze-van der Honing 2011).
Foodborne transmission can be avoided by cooking meat above 60°C, which
inactivates the virus (Emerson 2005).
Figure 1. Worldwide distribution of HEV genotypes.
Diagnosis of hepatitis E
In immmunocompetent patients the diagnosis of hepatitis E is based on the
detection of HEV-specific antibodies. While IgG antibodies indicate acute and past
HEV infections, IgM antibodies can only be found in patients with acute infections
(Pischke and Wedemeyer 2010). There are different commercial assays available for
detection of HEV-specific antibodies. Comparison of six of these assays revealed a
wide variation of diagnostic sensitivities and specificities as well as interassay
disagreements (Drobeniuc 2010). Thus, some of the remarkable discrepancies in
HEV seroprevalence rates reported in different studies may be explained by varying
sensitivities of the respective assays.
HEV-specific IgG antibodies can be detected in patients with previous contact
with HEV. They do not differentiate between ongoing HEV infection and past
contact with the virus. To prove current infection the detection of HEV RNA by
PCR has been established. Numerous assays using different primers have been
Hepatitis E: an underestimated problem?  57
developed (Meng 1999, Zhao 2007). Furthermore, few quantitative PCR assays
have been described (Ahn 2006, Enouf 2006).
In immunocompromised individuals, diagnosis of HEV infection may only be
based on the detection of HEV RNA as seroassays lack sensitivity especially in the
early phase of infection (Pischke 2010c). HEV RNA can not only be detected in
serum samples but also in stool (Pischke 2010b) and thus infectivity of HEV
infected persons can be determined by investigating stool for HEV RNA.
Worldwide distribution of HEV infections
In the last few years an increasing frequency of diagnosed cases of HEV infections
has been reported from various industrialised countries (Pischke 2010b). The
presence of HEV RNA in urban sewage samples from Spain, the US and France has
been shown, suggesting that HEV may be more prevalent in industrialised countries
than previously assumed (Clemente-Casares 2003). In each of these three countries
it was possible to discover HEV contamination in sewage samples in a notably high
frequency. These findings may partially explain the huge gap between
seroprevalence rates and the rather low numbers of diagnosed and reported cases of
acute hepatitis E in Western countries. For example, Germany has a seroprevalence
rate of 2% in a population of 80 million individuals (representing 1.6 million
persons with possible previous HEV infection) but only about 200 cases of hepatitis
E are diagnosed and reported each year (Pischke 2011a, Pischke 2010b). The
mismatch between high seroprevalence rates and the low number of symptomatic
cases has also been investigated in a recent study from Egypt. 919 anti-HEV
seronegative individuals from rural Egypt were followed and, interestingly, 3.7%
(n=34) of these individuals seroconverted to anti-HEV within 11 months of follow
up (Stoszek 2006). However, none of these 34 individuals suffered from
symptomatic hepatitis E. This finding corresponds with data from a recently
published large vaccine study performed in China where very few of the patients in
the placebo group who seroconverted during a follow-up period developed
symptomatic acute hepatitis E (Zhu 2010). Overall, these data suggest that far less
than 5% of all contacts with HEV lead to symptomatic hepatitis E (Wedemeyer and
Pischke 2011).
Even so, a rapid increase in reported HEV infections has been recognized in
several industrialized countries over the last 10 years. To investigate the potential
underlying reasons for this phenomenon, we analyzed the time trend of the anti-HEV seroprevalence in healthy German individuals versus the number of reported
cases of acute hepatitis E. Even though the number of reported cases increased more
than 5-fold over the last ten years (Figure 1), the anti-HEV IgG seroprevalence rate
remained rather stable over the last 15 years (Pischke 2011a). In contrast, the
number of scientific articles on HEV infections published in PubMed increased
sharply during the same period (Figure 1). These findings could indicate that the
increase of reported HEV cases in Germany and other industrialized countries is
based on an increased awareness associated with more frequent diagnosis of
hepatitis E but not a true increase in incidence rates (Pischke 2011a).
58  Hepatology 2012
Figure 2. Number of reported HEV infections in Germany over the last decade (Figure 2a)
and number of publications on HEV over the same time period (Figure 2b).
Transmission of HEV
The vast majority of HEV infections worldwide happens via the faecal-oral route
(Figure 2). Patient-to-patient transmission is very rare but has been described from a
large outbreak in Northern Uganda (Teshale 2011) and from hematology wards in
Europe (Pischke 2010b). Bloodborne transmission of HEV has been suggested in
the late nineties (Fainboim 1999). Subsequent studies from Hong Kong, Japan,
Great Britain and France confirmed blood transfusions as a possible source of HEV
transmission (Pischke 2010b). A single case of HEV  transmission by
transplantation of a liver graft from a patient with occult hepatitis E has been
reported (Schlosser 2011).
Zoonotic transmission of HEV has recently been assumed to be the main source
of HEV infections in industrialized countries (Figure 3). Both direct contact with
HEV-infected domestic animals and foodborne transmission are possible (Pischke
2010b). Commercial food products such as pig meat may be contaminated with
HEV as shown in studies from the Netherlands, France and Germany (Colson 2010,
Melenhorst 2007, Wenzel 2011). Meat should be heated to over 70°C to prevent
foodborne HEV infections (Emerson 2005). 
Hepatitis E: an underestimated problem?  59
Figure 3. Possible sources of HEV infection.
Acute hepatitis E in immunocompetent individuals
In the vast majority of cases, contact with HEV takes an asymptomatic course
(Stoszek 2006, Wedemeyer and Pischke 2011), especially if the contact happens
during childhood (Buti 2008). Immunocompetent individuals should be able to clear
the virus spontaneously. In symptomatic cases the incubation period of HEV
infections ranges from three to eight weeks with a mean of 40 days (Pischke 2010b).
The peak of HEV viremia can be detected in the early phase of infection while the
peak of ALT elevations usually occurs around 6 weeks after infection (Pischke
2010b).
Initial symptoms in acute hepatitis E are typically unspecific and can include flu-like myalgia, arthralgia, weakness and vomiting. In some patients jaundice, itching,
uncoloured stool and darkened urine occur accompanied by elevation of liver
transaminases, bilirubin, alkaline phosphatase and gamma-glutamyltransferase.
HEV infection can lead to more severe acute liver disease in pregnant women or
patients with underlying chronic liver diseases progressing to fulminant hepatic
failure in individual cases (Pischke 2010b). Possible explanations for the severe
courses in pregnant women are hormonal and immunological changes during
pregnancy (Navaneethan 2008). Recently an association between reduced
expression of the progesterone receptor and fatal outcome of hepatitis E in pregnant
women has been reported (Bose 2011).
Single cases of prolonged courses of HEV infection  in immunocompetent
individuals with up to two years of viremia have been described in the US (Mallet
2010), Spain (Gonzalez Tallon 2011) and China (Liu and Liu 2011). However, no
case of HEV-associated liver cirrhosis or development of hepatocellular carcinoma
has been reported in immunocompetent individuals.