Book on hepatitis from page 34 to
45
Hepatitis B 35
and donor testing strategies. In low prevalence areas it is estimated to be one to four
per million blood components transfused (Dodd 2000, Polizzotto 2008). In high
prevalence areas it is considerably higher (around 1 in 20,000) (Shang 2007,
Vermeulen 2011).
There are different strategies for donor screening. Most countries use HBsAg
screening of donors. Others, like the United States, use both HBsAg and anti-HBc.
Routine screening of anti-HBc remains controversial, as the specificity is low and
patients with cleared hepatitis have to be excluded. Screening of pooled blood
samples or even individual samples may be further improved by nucleic acid
amplification techniques. However, this is an issue of continuous debate due to
relatively low risk reduction and associated costs.
Nosocomial infection
Nosocomial infection can occur from patient to patient, from patient to health care
worker and vice versa. HBV is considered the most commonly transmitted blood-borne virus in the healthcare setting.
In general, nosocomial infection of hepatitis B can and should be prevented.
Despite prevention strategies, documented cases of nosocomial infections do occur
(Williams 2004). However, the exact risk of nosocomial infection is unknown. The
number of infected patients reported in the literature is likely to be an underestimate
of true figures as many infected patients may be asymptomatic and only a fraction
of exposed patients are recalled for testing.
Strategies to prevent nosocomial transmission of hepatitis B:
− use of disposable needles and equipment,
− sterilization of surgical instruments,
− infection control measures, and
− vaccination of healthcare workers.
Due to the implementation of routine vaccination of health care workers the
incidence of HBV infection among them is lower than in the general population
(Duseja 2002, Mahoney 1997). Therefore, transmission from healthcare workers to
patients is a rare event, while the risk of transmission from an HBV-positive patient
to a health care worker seems to be higher.
Healthcare workers positive for hepatitis B are not generally prohibited from
working. However, the individual situation has to be evaluated in order to decide on
the necessary measures. Traditionally, HBeAg-negative healthcare workers are
considered not to be infective, whereas HBeAg-positive healthcare workers should
wear double gloves and not perform certain activities, to be defined on an individual
basis. However, there have been cases of transmission of hepatitis B from HBsAg-positive, HBeAg-negative surgeons to patients (Teams 1997). Hepatitis B virus has
been identified with a precore stop codon mutation resulting in non-expression of
HBeAg despite active HBV replication. Therefore, HBV DNA testing has been
implemented in some settings, although this may not always be reliable due to
fluctuating levels of HBV DNA. In most developed countries guidelines for
hepatitis B positive healthcare workers have been established and should be
consulted.
36 Hepatology 2012
Organ transplantation
Transmission of HBV infection has been reported after transplantation of
extrahepatic organs from HBsAg positive donors (e.g., kidney, cornea) (Dickson
1997). Therefore, organ donors are routinely screened for HBsAg. The role of anti-HBc is controversial, as it is in screening of blood donors. Reasons are the
possibility of false positive results, the potential loss of up to 5% of donors even in
low endemic areas, and the uncertainty about the infectivity of organs, especially
extrahepatic organs, from donors who have isolated anti-HBc (Dickson 1997).
There is an increased risk of HBV infection for the recipient if organs of such
donors are transplanted as compared to anti-HBc negative donors.
Postexposure prophylaxis
In case of exposure to HBV in any of the circumstances mentioned above,
postexposure prophylaxis is recommended for all non-vaccinated persons. A
passive-active immunization is recommended. The first dose of active immunization
should be given as early as possible. 12 hours after the exposure is usually
considered the latest time point for effective postexposure prophylaxis. One dose of
hepatitis B-immunoglobulin (HBIG) should be administered at the same time, if the
source is known to be HBsAg-positive. The other two doses of vaccine should be
administered according to the usual schedule.
Vaccinated individuals with a documented response do not need postexposure
prophylaxis. Individuals who have had no post-vaccination testing should be tested
for anti-HBs titer as soon as possible. If this is not possible, or the anti-HBs titer is
insufficient (<100 IU/l), they will require a second course of vaccination.
Individuals who are documented non-responders will require two doses of HBIG
given one month apart.
Natural history and clinical manifestations
The spectrum of clinical manifestations of HBV infection varies in both acute and
chronic disease. During the acute phase, manifestations range from subclinical or
anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis. During
the chronic phase, manifestations range from an asymptomatic carrier state to
chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic
manifestations can occur in both acute and chronic infection.
Acute hepatitis
After HBV transmission, the incubation period lasts from one to four months. A
prodromal phase may appear before acute hepatitis develops. During this period a
serum sickness-like syndrome may develop. This syndrome manifests with fever,
skin rash, arthralgia and arthritis. It will usually cease with the onset of hepatitis. At
least 70% of patients will then have subclinical or anicteric hepatitis, while less than
30% will develop icteric hepatitis. The most prominent clinical symptoms of
hepatitis are right upper quadrant discomfort, nausea, jaundice and other unspecific
constitutional symptoms. In case of coinfection with other hepatitis viruses or other
underlying liver disease the clinical course may be more severe. The symptoms
including jaundice generally disappear after one to three months, but some patients
Hepatitis B 37
have prolonged fatigue even after normalisation of serum aminotransferase
concentrations.
Concentrations of alanine and aspartate aminotransferase levels (ALT and AST)
may rise to 1000-2000 IU/L in the acute phase. ALT is typically higher than AST.
Bilirubin concentration may be normal in a substantial portion of patients. In
patients who recover, normalisation of serum aminotransferases usually occurs
within one to four months. Persistent elevation of serum ALT for more than six
months indicates progression to chronic hepatitis.
The rate of progression from acute to chronic hepatitis B is primarily determined
by the age at infection (Ganem 2004, McMahon 1985). In adult-acquired infection
the chronicity rate is 5% or less, whereas it is higher if acquired at younger ages. It
is estimated to be approximately 90% for perinatally-acquired infection, and 20-50% for infections between the ages of one and five years.
Until recently it was assumed that patients who recover from acute hepatitis B
actually clear the virus from the body. However, there is a lot of evidence now
suggesting that even in patients positive for anti-HBs and anti-HBc HBV DNA may
persist lifelong in the form of covalently closed circular DNA (cccDNA) and this
latent infection maintains the T cell response that keeps the virus under control
(Yotsuyanagi 1998, Guner 2011). Complete eradication rarely occurs. This is an
important finding, as immunosuppression can lead to reactivation of the virus, e.g.,
after organ transplant or during chemotherapy.
Fulminant hepatic failure is unusual, occurring in approximately 0.1-0.5% of
patients. Reasons and risk factors for fulminant hepatitis B are not well understood
(Garfein 2004). There may be correlation with substance abuse or coinfections with
other viruses. Fulminant hepatitis B is believed to be due to massive immune-mediated lysis of infected hepatocytes. This is why many patients with fulminant
hepatitis B have no evidence of HBV replication at presentation.
Antiviral treatment of patients with acute hepatitis B usually is not recommended
(Cornberg 2011). In adults, the likelihood of fulminant hepatitis B is less than 1%,
and the likelihood of progression to chronic hepatitis B is less than 5%. Therefore,
treatment of acute hepatitis B is mainly supportive in the majority of patients.
Treatment can be considered in certain subsets of patients, e.g., patients with a
severe or prolonged course of hepatitis B, patients coinfected with other hepatitis
viruses or underlying liver diseases, patients with immunosuppression, or patients
with fulminant liver failure undergoing liver-transplantation (Kondili 2004,
Tillmann 2006). However, early intervention may interfere with the immune
response and decrease the likelihood of immune control of HBV infection, thus
facilitating chronicity (Tillmann 2006).
In addition, contacts of the patient should be checked for exposure to hepatitis B.
Chronic hepatitis
The HBV chronicity rate is around 5% or less in adult-acquired infection, as
mentioned earlier. In perinatally-acquired infection it is estimated to be
approximately 90%, and 20-50% for infections between the age of one and five
years (Ganem 2004, McMahon 1985). Most patients will not have a history of acute
hepatitis.
Most patients with chronic hepatitis B are clinically asymptomatic. Some may
have nonspecific symptoms such as fatigue. In most instances, significant clinical
38 Hepatology 2012
symptoms will develop only if liver disease progresses to decompensated cirrhosis.
In addition, extrahepatic manifestations may cause symptoms.
Accordingly, physical examination will be normal in most instances. In advanced
liver disease there may be stigmata of chronic liver disease such as splenomegaly,
spider angiomata, caput medusae, palmar erythema, testicular atrophy,
gynecomastia, etc. In patients with decompensated cirrhosis, jaundice, ascites,
peripheral edema, and encephalopathy may be present.
Laboratory testing shows mild to moderate elevation in serum AST and ALT in
most patients, whereas normal transaminases occur rarely. During exacerbation,
serum ALT concentration may be as high as 50 times the upper limit of normal.
Alfa-fetoprotein concentrations correlate with disease activity. In exacerbations of
hepatitis B, concentrations as high as 1000 ng/mL may be seen.
The natural course of chronic HBV infection is determined by the interplay of
viral replication and the host immune response. Other factors that may play a role in
the progression of HBV-related liver disease include gender, alcohol consumption,
and concomitant infection with other hepatitis virus(es). The outcome of chronic
HBV infection depends upon the severity of liver disease at the time HBV
replication is arrested. Liver fibrosis is potentially reversible once HBV replication
is controlled.
There are two different states that are distinguished in chronic HBV infection:
first, a high-replicative state with active liver disease and elevated serum ALT.
HBV DNA and HBeAg are present. Second, a low or non-replicative phase, where
serum ALT may normalize, HBeAg disappears, and anti-HBe antibodies appear. In
some patients, viral replication stops completely, as demonstrated by sensitive HBV
DNA assays, although they remain HBsAg-positive. These patients have
undetectable HBV DNA in serum and normal ALT concentrations. No sign of
ongoing liver damage or inflammation is found on liver biopsy. This state is called
inactive carrier state.
A small percentage of patients continue to have moderate levels of HBV
replication and active liver disease (elevated serum ALT and chronic inflammation
on liver biopsies) but remain HBeAg negative. These patients with HBeAg-negative
chronic hepatitis may have residual wild type virus or HBV variants that cannot
produce HBeAg due to precore or core promoter variants.
The first high-replicative phase may switch into the non-replicative phase either
spontaneously or upon antiviral treatment. Conversely, the non-replicative phase
may reactivate to the high-replicative phase either spontaneously or with
immunosuppression (e.g., in HIV infection or with chemotherapy).
In perinatally-acquired chronic HBV infection there are three different states: An
immune tolerance phase, an immune clearance phase, and a late non-replicative
phase.
The immune tolerance phase, which usually lasts 10-30 years, is characterized by
high levels of HBV replication, as manifested by the presence of HBeAg and high
levels of HBV DNA in serum. However, there is no evidence of active liver disease
as seen by normal serum ALT concentrations and minimal changes in liver biopsy.
It is thought that this lack of liver disease despite high levels of HBV replication is
due to immune tolerance to HBV (Dienstag 2008), although the exact mechanisms
are unknown. This phenomenon of immune tolerance is believed to be the most
important reason for the poor response to interferon therapy in HBeAg-positive
Hepatitis B 39
patients with normal ALT levels. During this phase there is a very low rate of
spontaneous HBeAg clearance. It is estimated that the rate of spontaneous HBeAg
clearance is only 15% after 20 years of infection.
During the second to third decade, the immune-tolerance phase may convert to
one of immune clearance. The spontaneous HBeAg clearance rate increases. It is
estimated to be 10 to 20% annually. If HBeAg seroconversion occurs, exacerbations
of hepatitis with abrupt increases in serum ALT are very often observed. These
exacerbations follow an increase in HBV DNA and might be due to a sudden
increase in immune-mediated lysis of infected hepatocytes. Most often there are no
clinical symptoms during exacerbation, and rise of ALT is only detected by routine
examinations. Some patients may develop symptoms mimicking acute hepatitis.
Titers of anti-HBc IgM may rise as well as alfa-fetoprotein. If such patients are not
known to be HBV-infected, misdiagnosis of acute hepatitis B can be made. HBeAg
seroconversion and clearance of HBV DNA from the serum is not always achieved
after exacerbation. In these patients recurrent exacerbation with intermittent
disappearance of serum HBV DNA with or without HBeAg loss may occur. The
non-replicative phase is usually characterized by the absence of HBV DNA and
normalisation of serum ALT, like in adult chronic HBV.
Very few patients with chronic HBV infection become HBsAg-negative in the
natural course of infection. The annual rate of HBsAg clearance has been estimated
to be less than 2% in Western patients and even lower (0.1-0.8%) in patients of
Asian origin (Liaw 1991) following an accelerated decrease in HBsAg levels during
the 3 years before HBsAg seroclearance (Chen 2011). If loss of HBsAg occurs,
prognosis is considered favourable. However, clearance of HBsAg does not exclude
development of cirrhosis or hepatocellular carcinoma in some patients, although the
exact rate of these complications is not known. This phenomenon is thought to be
linked to the fact that HBV DNA may still be present in hepatocytes despite HBsAg
loss.
Prognosis and survival
As clinical course varies among patients, there is a wide variation in clinical
outcome and prognosis of chronic HBV infection. The lifetime risk of a liver-related
death has been estimated to be 40-50% for men and 15% for women. The risk of
progression appears to be higher if immune activation occurs. The estimated five-year rates of progression (Fattovich 2008):
− Chronic hepatitis to cirrhosis – 10-20%
− Compensated cirrhosis to hepatic decompensation – 20-30%
− Compensated cirrhosis to hepatocellular carcinoma – 5-15%
Accordingly, the survival rates are:
− Compensated cirrhosis - 85% at five years
− Decompensated cirrhosis - 55-70% at one year and 15-35% at five years
Viral replication
In patients with signs of viral replication (i.e., HBeAg-positive) survival is
consistently worse than in patients who are HBeAg-negative. However, in recent
decades, infections with HBeAg-negative precore mutants prevail by far in newly-acquired infections, resulting in a different pattern of HBeAg-negative and HBV
DNA-positive hepatitis with fibrosis progression and HCC in a substantial
40 Hepatology 2012
proportion of patients. In recent years, the amount of HBV DNA has also been
linked to disease progression and has replaced HBeAg-positivity as a marker for
disease activity (Chen 2006). This is true both for progression to cirrhosis as well as
for the risk of HCC. Therefore, most treatment guidelines today are based on the
level of HBV viremia. A reasonable cut-off to distinguish patients with a low risk of
progression from patients with a high risk and indication for antiviral treatment is
10
4
copies/ml (corresponding to approximately 2 x 10
3
IU/ml) (Cornberg 2011),
although other cut-offs may be used.
The duration of viral replication is obviously linked with the risk of development
of cirrhosis and HCC. As necroinflammation may persist longer in patients with a
prolonged replicative phase, the risk of disease progression is elevated. Conversely,
even in patients with decompensated cirrhosis, suppression of HBV replication and
delayed HBsAg clearance can result in improvement in liver disease (Fung 2008).
Alcohol use
HBV infection in heavy alcohol users is associated with faster progression to liver
injury and an elevated risk of developing cirrhosis and HCC (Bedogni 2008,
Marcellin 2008). Survival is reduced compared to HBV-negative heavy alcohol
users. However, there is no clear evidence that heavy alcohol use is associated with
an enhanced risk of chronic HBV infection, although prevalence of HBV is
estimated to be fourfold higher than in controls (Laskus 1992) with variation among
regions and cohorts (Rosman 1996).
Hepatitis C coinfection
If coinfection of HCV and HBV occurs, HCV usually predominates. This may lead
to lower levels of transaminases and HBV DNA (Jardi 2001). The rate of HBsAg
seroconversion even appears to be increased, although this finding may be due to
the fact that around one third of patients coinfected with HBV and HCV lack
markers of HBV infection (i.e., HBsAg) although HBV DNA is detectable. Despite
lower aminotransferases and HBV DNA levels, liver damage is worse in most
instances. The risks of severe hepatitis and fulminant hepatic failure seem to be
elevated if both infections occur simultaneously regardless of whether it is an acute
coinfection of HBV and HCV or acute hepatitis C in chronic hepatitis B (Liaw
2004).
Hepatitis D coinfection
Acute HBV and HDV coinfection tends to be more severe than acute HBV infection
alone. It is more likely to result in fulminant hepatitis. If HDV superinfection in
patients with chronic HBV infection occurs, HDV usually predominates, and HBV
replication is suppressed (Jardi 2001). Severity of liver disease is worse and
progression to cirrhosis is accelerated (Fattovich 2000, Grabowski 2010).
It is very difficult to predict the individual course of hepatitis B due to the many
factors influencing disease progression. 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
is used routinely in the clinic at present. In patients with cirrhosis, the MELD-score
(Model for End-Stage Liver Disease) and the CHILD-Pugh score are used (see
Chapter 3).
Hepatitis B 41
Extrahepatic manifestations
The two major extrahepatic complications of chronic HBV are polyarteritis nodosa
and glomerular disease. They occur in 10-20% of patients with chronic hepatitis B
and are thought to be mediated by circulating immune complexes (Han 2004).
Polyarteritis nodosa
The clinical manifestations are similar to those in patients with polyarteritis who are
HBV-negative. There may be some clinical benefit to antiviral therapy.
Nephropathy/Glomerulonephritis
HBV can induce both membranous nephropathy and, less often,
membranoproliferative glomerulonephritis. Most cases occur in children. The
clinical hallmark is proteinuria. In contrast to polyarteritis nodosa, there is no
significant benefit of antiviral treatment.
For further details, please refer to extrahepatic manifestations in Chapter 16.
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44 Hepatology 2012
3. Hepatitis C
Christoph Boesecke and Jan-Christian Wasmuth
Epidemiology
Hepatitis C is a disease with a significant global impact. According to the World
Health Organization there are 130-170 million people infected with the hepatitis C
virus (HCV), corresponding to 2-2.5% of the world’s total population. There are
considerable regional differences. In some countries, e.g., Egypt, the prevalence is
as high as 22% (WHO 2011). In Africa and the western Pacific the prevalence is
significantly higher than in North America and Europe (RKI 2004).
It is estimated that there are 2-5 million HCV-positive persons in Europe. The
prevalence of HCV antibodies in otherwise healthy blood donors is approximately
1.6% in the United States, 1.15% in Italy, 0.4% in Germany, and 0.23% in
Scandinavia (RKI 2004, Hatzakis 2011). The number of patients HCV RNA-positive is estimated to be around 80 to 90% of all HCV antibody-positive persons.
Certain groups are preferentially affected: The highest risk factor in most cases is
injection drug use. But patients undergoing hemodialysis and persons who received
blood transfusions before 1991 are at risk also. In Europe and the United States
chronic hepatitis C is the most common chronic liver disease and the majority of
liver transplants performed are for chronic HCV.
It is difficult to determine the number of new HCV infections, as most acute cases
will not be noticed clinically. Fewer than 25% of acute cases of hepatitis C are
clinically apparent (Vogel 2009). In addition, the age of infection upon diagnosis is
not possible to determine in most cases. Nevertheless, it has to be assumed that the
number of new infections has considerably decreased over the past decades. For the
United States it is estimated that the number of new cases of acute HCV infection
has fallen from approximately 230,000 per year in the 1980s to about 20,000 cases
per year currently (Wasley 2008). This decrease is primarily associated with
reduced infections in injection drug users, a probable consequence of changes in
injection practices motivated by education about human immunodeficiency virus
(HIV) transmission. Transfusion-associated hepatitis C has had little impact on this
decline, as the number of cases has been reduced almost to zero. The only different
trend is an increase in acute hepatitis C infections in HIV-positive men who have
sex with men (MSM) globally over the last decade (Boesecke 2011).
Hepatitis C 45
Transmission
Parenteral exposure to the hepatitis C virus is the most efficient means of
transmission. The majority of patients infected with HCV in Europe and the United
States acquired the disease through intravenous drug use or blood transfusion. The
latter has become rare since routine testing of the blood supply for HCV began in
the early 1990s. Other types of parenteral exposure are important in specific regions
in the world.
The following possible routes of infection have been identified in anti-HCV-positive blood donors (in descending order of transmission risk):
− Injection drug use
− Blood transfusion
− Sex with an intravenous drug user
− Having been in jail more than three days
− Religious scarification
− Having been struck or cut with a bloody object
− Pierced ears or body parts
− Immunoglobulin injection
Very often in patients with newly diagnosed HCV infection no clear risk factor
can be identified.
Injection drug use
Injection drug use has been the most commonly identified source of acute HCV
infection. It is estimated that most newly acquired infections occur in individuals
who have injected illegal drugs. The seroprevalence of anti-HCV antibodies in
groups of intravenous drug users may be up to 70% with considerable variation
depending on factors such as region, risk behaviour, socioeconomic status, etc,
underscoring the efficiency of transmission via direct blood contact (Sutton 2008).
HCV infection also has been associated with a history of intranasal cocaine use,
presumably due to blood on shared straws or other sniffing paraphernalia. This may
explain partly the recent increase in cases of acute HCV infections in HIV-positive
MSM (Schmidt 2011).
Blood transfusion
In the past, blood transfusion or use of other blood products was a major risk factor
for transmission of HCV. In some historic cohorts 10% or more of patients who
received blood transfusions were infected with hepatitis C (Alter 1989). However,
blood donor screening for HCV since the early 1990s has nearly eliminated this
transmission route. Blood donors are screened for anti-HCV antibodies and HCV
RNA – at least in developed countries. The risk is now estimated to be between
1:500,000 and 1:1,000,000 units (Pomper 2003).
In cohorts of multiply transfused patients such as hemophiliacs, over 90% of
patients were infected with hepatitis C in the past (Francois 1993). Since the use of
routine inactivated virus (e.g., heat inactivation or pasteurization) or recombinant
clotting factors, new cases of hepatitis C infection have become uncommon in these
patients.
