Book on hepatitis from page 30 to 35

Book on hepatitis from page 30 to 35

30. Acute Liver Failure  526
Akif Altinbas, Lars P. Bechmann, Hikmet Akkiz, Guido Gerken, Ali Canbay  526
Introduction and definition  526
Epidemiology and etiologies  526
Intoxication  527
Amanita intoxication  528
Viral hepatitis  529
Immunologic etiologies  529
Wilson’s Disease  529
Vascular disorders  529
Pregnancy-induced liver injury  530
Undetermined  530
25
Molecular mechanisms and clinical presentation  530
Prognosis  532
Treatment  533
General management  533
Hepatic encephalopathy  533
Coagulopathy  534
Liver Transplantation  534
Extracorporal liver support systems  534
Specific treatment options  535
References  536
26  Hepatology 2012
Hepatitis A  27
1.  Hepatitis A
Sven Pischke and Heiner Wedemeyer
The virus
Hepatitis A is an inflammatory liver disease caused by infection with the hepatitis A
virus (HAV). HAV is a single-stranded 27 nm non-enveloped, icosahedral RNA
virus, which was first identified by immune electron microscopy in 1973 (Feinstone
1973). The virus belongs to the hepadnavirus genus of the Picornaviridiae.
Seven different HAV genotypes have been described, of which four are able to
infect humans (Lemon 1992).
The positive-sense single-stranded HAV RNA has a length of 7.5 kb and consists
of a a 5’ non-coding region of 740 nucleotides, a coding region of 2225 nucleotides
and a 3’ non-coding region of approximately 60 nucleotides.
Epidemiology
HAV infections occur worldwide, either sporadically or in epidemic outbreaks. An
estimated 1.4 million cases of HAV infections occur each year. HAV is usually
transmitted and spread via the fecal-oral route (Lemon 1985). Thus, infection with
HAV occurs predominantly in areas with lower socio-economic status and reduced
hygienic standards, especially in developing, tropical countries. In industrialised
countries like the US or Germany the number of reported cases has decreased
markedly in the past decades, according to official data published by the Centers for
Disease Control and Prevention (CDC, Atlanta, USA) and the Robert Koch Institute
(RKI, Berlin, Germany) (Figure 1). This decrease is mainly based on improved
sanitary conditions and anti-HAV vaccination. Vaccination programs have also
resulted in fewer HAV infections in various endemic countries including Argentina,
Brazil, Italy, China, Russia, Ukraine, Spain, Belarus, Israel and Turkey (Hendrickx
2008).
Transmission
HAV is usually transmitted fecally-orally either by person-to-person contact or
ingestion of contaminated food or water. Five days before clinical symptoms
appear, the virus can be isolated from feces of patients (Dienstag 1975). The
hepatits A virus usually stays detectable in the feces up to two weeks after the onset
28  Hepatology 2012
of jaundice. Fecal excretion of HAV up to five months after infection can occur in
children and immunocompromised persons.
Risk groups for acquiring an HAV infection in Western countries are health care
providers, military personnel, psychiatric patients and men who have sex with men.
Parenteral transmission by blood transfusion has been described but is a rare event.
Mother-to-fetus transmission has not been reported (Tong 1981).
Figure 1. Number of reported cases of HAV infections in the USA and Germany
within the last decade. (Sources: CDC and Robert Koch Institut, data for 2010 for the
US are not yet available.)
Clinical course
The clinical course of HAV infection varies greatly, ranging from asymptomatic,
subclinical infections to cholestatic hepatitis or fulminant liver failure. Most
infections in children are either asymptomatic or unrecognized while 70% of adults
develop clinical symptoms of hepatitis with jaundice and hepatomegaly.
The incubation time ranges between 15 to 49 days with a mean of approximately
30 days (Koff 1992). Initial symptoms are usually non-specific and include
weakness, nausea, vomiting, anorexia, fever, abdominal discomfort, and right upper
quadrant pain (Lednar 1985). As the disease progresses, some patients develop
jaundice, darkened urine, uncoloured stool and pruritus. The prodromal symptoms
usually diminish when jaundice appears.
Approximately 10% of infections take a biphasic or relapsing course. In these
cases the initial episode lasts about 3-5 weeks, followed by a period of biochemical
remission with normal liver enzymes for 4-5 weeks. Relapse may mimic the initial
episode of the acute hepatitis and complete normalization of ALT and AST values
may take several months. (Tong 1995).
Hepatitis A  29
Cases of severe fulminant HAV infection leading to hepatic failure occur more
often in patients with underlying liver disease. Conflicting data on the course of
acute hepatitis A have been reported for patients with chronic hepatitis C. While
some studies showed a higher incidence of fulminant hepatitis (Vento 1998), other
studies do not confirm these findings and even suggest that HAV superinfection
may lead to clearance of HCV infection (Deterding 2006). Other risk factors for
more severe courses of acute hepatitis A are age, malnutrition and
immunosuppression.
In contrast to hepatitis E, there are no precise data on the outcome of HAV
infection during pregnancy. Some data suggest an increased risk of gestational
complications and premature birth (Elinav 2006).
HAV infection has a lethal course in 0.1% of children, in 0.4% of persons aged
15-39 years, and in 1.1% in persons older than 40 years (Lemon 1985). In contrast
to the other fecally-orally transmitted hepatitis, hepatitis E, no chronic courses of
HAV infection have been reported so far.
Extrahepatic manifestations
Extrahepatic manifestations are uncommon in HAV (Pischke 2007). If they occur,
extrahepatic symptoms usually show an acute onset and disappear upon resolution
of HAV infection in most cases. Possible extrahepatic manifestations of acute HAV
infection are arthralgia, diarrhea, renal failure, red cell aplasia, generalised
lymphadenopathy, and pancreatitis. Arthralgia can be found in 11% of patients with
hepatitis A.
Very uncommon are severe extrahepatic manifestations like pericarditis and/or
renal failure. An association of hepatitis A with cryoglobulinemia has been reported
but is a rare event (Schiff 1992). Furthermore, cutaneous vasculitis can occur. In
some cases, skin biopsies reveal anti-HAV-specific IgM antibodies and
complements in the vessel walls (Schiff 1992). In contrast to hepatitis B or C, renal
involvement is rare, and there are very few case reports showing acute renal failure
associated with HAV infection (Pischke 2007). Recently it has been shown that
approximately 8% of hepatitis A cases are associated with acute kidney injury (Choi
2011).
Diagnosis
Diagnosis of acute HAV infection is based on the detection of anti-HAV IgM
antibodies or HAV RNA. The presence of HAV IgG antibodies can indicate acute
or previous HAV infection. HAV IgM and IgG antibodies also become positive
early after vaccination, with IgG antibodies persisting for at least two to three
decades after vaccination. Available serological tests show a very high sensitivity
and specificity.
Delayed seroconversion may occur in immunocompromised individuals, and
testing for HAV RNA should be considered in immunosuppressed individuals with
unclear hepatitis. HAV RNA testing of blood and stool can determine if the patient
is still infectious. However, it has to be kept in mind that various in-house HAV
RNA assays may not be specific for all HAV genotypes and thus false-negative
results can occur.
30  Hepatology 2012
Elevated results for serum aminotransferases and serum bilirubin can be found in
symptomatic patients (Tong 1995). ALT levels are usually higher  than serum
aspartate aminotransferase (AST) in non-fulminant cases. Increased serum levels of
alkaline phosphatase and gamma-glutamyl transferase indicate a cholestatic form of
HAV infection. The increase and the peak of serum aminotransferases usually
precede the increase of serum bilirubin. Laboratory markers of inflammation, like
an elevated erythrocyte sedimentation rate and increased immunoglobulin levels,
can also frequently be detected.
Treatment and prognosis
There is no specific antiviral therapy for treatment of hepatitis A. The disease
usually takes a mild to moderate course, which requires no hospitalisation, and only
in fulminant cases is initiation of symptomatic therapy necessary. Prolonged or
biphasic courses should be monitored closely. HAV may persist for some time in
the liver even when HAV RNA becomes negative in blood and stool (Lanford
2011), which needs to be kept in mind for immunocompromised individuals. Acute
hepatitis may rarely proceed to acute liver failure; liver transplantation is required in
few cases. In the US, 4% of all liver transplantations performed for acute liver
failure were due to hepatitis A (Ostapowicz 2002). In a cohort of acute liver failures
at one transplant center in Germany approximately 1% of patients suffered from
HAV infection (Hadem 2008). The outcome of patients after liver transplantation
for fulminant hepatitis A is excellent. Timely referral to liver transplant centers is
therefore recommended for patients with severe or fulminant hepatitis A.
References
Choi HK, Song YG, Han SH, et al. Clinical features and outcomes of acute kidney injury among
patients with acute hepatitis A. J Clin Virol 2011;52:192-7. (Abstract)
Deterding K, Tegtmeyer B, Cornberg M, et al. Hepatitis A virus infection suppresses hepatitis C
virus replication and may lead to clearance of HCV. J Hepatol 2006;45:770-8.
(Abstract)
Dienstag JL, Feinstone SM, Kapikian AZ, Purcell RH. Faecal shedding of hepatitis-A antigen.
Lancet 1975;1:765-7.
Elinav E, Ben-Dov IZ, Shapira Y, et al. Acute hepatitis A infection in pregnancy is associated
with high rates of gestational complications and preterm labor. Gastroenterology
2006;130:1129-34. (Abstract)
Feinstone SM, Kapikian AZ, Purceli RH. Hepatitis A: detection by immune electron microscopy
of a viruslike antigen associated with acute illness. Science 1973;182:1026-8.
(Abstract)
Hadem J, Stiefel P, Bahr MJ, et al. Prognostic implications of lactate, bilirubin, and etiology in
German patients with acute liver failure. Clin Gastroenterol Hepatol 2008;6:339-45.
(Abstract)
Hendrickx G, Van Herck K, Vorsters A, et al. Has the time come to control hepatitis A globally?
Matching prevention to the changing epidemiology. J Viral Hepat 2008;15 Suppl 2:1-15. (Abstract)
Koff RS. Clinical manifestations and diagnosis of hepatitis A virus infection. Vaccine 1992;10
Suppl 1:S15-7. (Abstract)
Lanford RE, Feng Z, Chavez D, et al. Acute hepatitis A virus infection is associated with a
limited type I interferon response and persistence of intrahepatic viral RNA. Proc Natl
Acad Sci U S A 2011;108:11223-8. (Abstract)
Lednar WM, Lemon SM, Kirkpatrick JW, Redfield RR, Fields ML, Kelley PW. Frequency of
illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol
1985;122:226-33. (Abstract)
Hepatitis A  31
Lemon SM, Jansen RW, Brown EA. Genetic, antigenic and biological differences between
strains of hepatitis A virus. Vaccine 1992;10 Suppl 1:S40-4. (Abstract)
Lemon SM. Type A viral hepatitis. New developments in an old disease. N Engl J Med
1985;313:1059-67. (Abstract)
Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver
failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-54. (Abstract)
Pischke S, Vogel, A. Jaeckel, E., Manns, M.P. Immunopathogenesis of Extrahepatic
Manifestations in HAV, HBV, and HCV Infections. In: Liver Immunology. Totowa,
New Jersey: Humana Press, 2007:209-17.
Schiff ER. Atypical clinical manifestations of hepatitis A. Vaccine 1992;10 Suppl 1:S18-20.
(Abstract)
Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a
community teaching hospital. J Infect Dis 1995;171 Suppl 1:S15-8. (Abstract)
Tong MJ, Thursby M, Rakela J, McPeak C, Edwards VM, Mosley JW. Studies on the maternal-infant transmission of the viruses which cause acute hepatitis. Gastroenterology
1981;80:999-1004. (Abstract)
Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus
superinfection in patients with chronic hepatitis C. N Engl J Med 1998;338:286-90.
(Abstract)
32  Hepatology 2012
2.  Hepatitis B
Christoph Boesecke and Jan-Christian Wasmuth
Introduction
It is estimated that approximately 30% of the world's population has had contact
with or are carriers of the hepatitis B virus (HBV). An estimated 350 million of
them are HBV carriers (Goldstein 2005). Thus, HBV infection is one of the most
important infectious diseases worldwide. Around one million persons die of HBV-related causes annually. There is a wide range of HBV prevalence rates in different
parts of the world. HBV prevalence varies from 0.1% up to 20%. Low prevalence
areas (0.1-2%) are Western Europe (with wide variation within Europe), United
States and Canada, Australia and New Zealand; intermediate prevalence (3-5%) are
the Mediterranean countries, Japan, Central Asia, the Middle East, and Latin and
South America; and high prevalence areas (10-20%) include southeast Asia, China,
and sub-Saharan Africa. This diversity is probably related to differences in age at
infection, which correlates with the risk of chronicity. The progression rate from
acute to chronic HBV infection decreases with age. It is approximately 90% for an
infection acquired perinatally, and is as low as 5% (or even lower) for adults
(Stevens 1975, Wasley 2008).
The incidence of new infections has decreased in most developed countries, most
likely due to the implementation of vaccination strategies (Rantala 2008). However,
exact data is difficult to generate as many cases remain undetected due to the
asymptomatic nature of many infections (RKI 2007, CDC 2010). Nevertheless, in
Germany 2524 cases of acute hepatitis B were documented in the year 2006,
corresponding to an incidence rate of 1.4 per 100,000 inhabitants. In 1997 there
were 6135 documented cases of acute hepatitis B. Likewise, the incidence of acute
hepatitis B in the United States has decreased by 78% from 1990 to 2005 (Wasley
2008). It is expected that this number will further decrease in countries with
implementation of vaccination programs. In Germany 87% of all children starting
school were fully vaccinated in 2006 with a trend toward increasing coverage
(Poethko-Muller 2007). Interestingly, recent data from a Swiss clinic indicate that
uptake in HBV vaccinations is significantly higher when vaccination is endorsed by
nurses rather than the patients’ physician (Blanco 2011).
Hepatitis B  33
Although the incidence of acute HBV infection has decreased in most countries
due to the implementation of vaccination programs, HBV-related complications
such as cancers and deaths have been on the increase (Gomaa 2008, Hatzakis 2011).
Reasons might be the delay of vaccination effects, improved diagnosis, and better
documentation of HBV cases. Although a drop in prevalence has been observed in
many countries, estimates are difficult due to a continuously growing migration
from high or medium prevalence areas to low prevalence areas (Belongia 2008).
Transmission
The routes of HBV transmission:
−  Sexual
−  Percutaneous (Intravenous Drug Use)
−  Perinatal
−  Horizontal
−  Transfusion
−  Nosocomial infection (including needle-stick injury)
−  Organ transplantation
There is considerable variation in the predominance of transmission modes in
different geographic areas. For example, in low prevalence areas such as Western
Europe, the routes are mainly unprotected sexual intercourse and intravenous drug
use. In high prevalence areas like sub-Saharan Africa perinatal infection is the
predominant mode of transmission. Horizontal transmission, particularly in early
childhood, is regarded as the major route of transmission in intermediate prevalence
areas.
Sexual transmission
In low prevalence areas sexual transmission is the major route of transmission.
Approximately 40% of new HBV infections in the United States is considered to be
transmitted via heterosexual intercourse, and 25% occurs in men who have sex with
men (MSM) (Wasley 2008). Measures to prevent HBV transmission are vaccination
and safer sex, i.e., use of condoms. However, there is ongoing debate regarding
what to advise low-viremic patients.
Percutaneous inoculation
Percutaneous transmission seems to be an effective mode of HBV transmission. The
most important route is sharing syringes and needles by intravenous drug users. In
low prevalence areas such as Europe and the United States about 15% of newly
diagnosed HBV infections is in the IVDU population (Wasley 2008). The risk of
HBV transmission increases with the number of years of drug use, frequency of
injection, and sharing of drug preparation equipment.
Other situations with possible percutaneous inoculation of HBV are sharing
shaving razors or toothbrushes, although the exact number remains unknown. In
addition, certain practices like acupuncture, tattooing, and body piercing have been
associated with transmission of hepatitis B. Public health education and the use of
disposable needles or equipment are important methods of prevention.
34  Hepatology 2012
Perinatal transmission
Transmission from an HBeAg-positive mother to her infant may occur in utero, at
the time of birth, or after birth. The rate of infection can be as high as 90%.
However, neonatal vaccination is highly efficacious (95%). Its efficacy indicates
that most infections occur at or shortly before birth. On the other hand, caesarean
section seems not be as protective as it is in other vertically transmitted diseases like
HIV.
The risk of transmission from mother to infant is related to the HBV replicative
rate in the mother. There seems to be a direct correlation between maternal HBV
DNA levels and the likelihood of transmission. In mothers with highly replicating
HBV the risk of transmission may be up to 85 to 90%, and continuously lowers with
lower HBV DNA levels (Burk 1994). In some studies there has been almost no
perinatal transmission if the mother has no significant ongoing replication (<10
5
log
copies/ml) (Li 2004).
It is possible to reduce the risk of perinatal transmission in several ways. The first
step is identification of persons at risk. Testing for HBsAg should be performed in
all women at the first prenatal visit and repeated later in pregnancy if appropriate
(CDC 2011). Newborns born to HBV-positive mothers can be effectively protected
by passive-active immunisation (>90% protection rate) (del Canho 1997, Dienstag
2008). Hepatitis B immunoglobulin for passive immunization should be given as
early as possible (within 12 hours), but can be given up to seven days after birth if
seropositivity of the mother is detected later. Active  immunisation follows a
standard regimen and is given at three time points (10 µg at day 0, month 1, and
month 6). Anti-HBV treatment of the mother with nucleoside analogs may be
discussed, especially in mothers with high HBV DNA levels, i.e., HBV DNA >10
6
copies/ml or 2x10
5
IU/ml. In one randomised, prospective, placebo-controlled
study, treatment of the mother with telbivudine resulted in prevention of almost all
cases of vertical transmission compared to a vertical transmission rate of about 10%
in the arm receiving only active and passive immunisation (Han 2011). Telbivudine
or tenofovir seem to be the treatment of choice. Adefovir and entecavir are not
recommended in pregnancy (Cornberg 2011).
As mentioned earlier, caesarean section should not be performed routinely, except
in cases of high viral load. If the child is vaccinated, (s)he may be breastfed (Hill
2002).
Horizontal transmission
Children may acquire HBV infection through horizontal transmission via minor
breaks in the skin or mucous membranes or close bodily contact with other children.
In addition, HBV can survive outside the human body for a prolonged period; as a
result, transmission via contaminated household articles such as toothbrushes, razors
and even toys may be possible. Although HBV DNA has been detected in various
bodily secretions of hepatitis B carriers, there is no firm evidence of HBV
transmission via body fluids other than blood.
Blood transfusion
Blood donors are routinely screened for hepatitis B surface antigen (HBsAg).
Therefore incidence of transfusion-related hepatitis B has significantly decreased.
The risk of acquiring post-transfusion hepatitis B depends on factors like prevalence