ASSOC PROF DR INGRID MIRON What is Viral Hepatitis Viral hepatitis is a systemic disease with primary inflammation of the liver by any one of a heterogenous group of hepatotropic viruses ID: 739803
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Slide1
CRONIC HEPATITIS, CIRRHOSIS, HEPATIC FAILURE
ASSOC. PROF. DR. INGRID MIRONSlide2
What is Viral Hepatitis ?
Viral hepatitis is a systemic disease with primary inflammation of the liver by any one of a
heterogenous group of hepatotropic viruses
2Slide3
Hepatitis Terms
Acute Hepatitis
: Short-term hepatitis.
Body’s immune system clears the virus from the body within 6 monthsChronic Hepatitis: Long-term hepatitis.Infection lasts longer than 6 months because the body’s immune system cannot clear the virus from the bodySlide4
HEPATITIS VIRUSES
Hepatitis A (HAV) Picornaviridae (1973)
Hepatitis B (HBV) Hepadnaviridae (1970)
Hepatitis C (HCV) Flaviviridae (1988)
Hepatitis D (HDV) ? (1977)
Hepatitis E (HEV) (Caliciviridae) (1983), Hepeviridae
Hepatitis F – Not separate entity – Mutant of B Virus.
Hepatitis G (HGV) Flaviviridae (1995
)
4Slide5
Viral Hepatitis - Historical Perspectives
“
Infectious”
5
A
Viral hepatitis
NA:NB
E
Enterically
transmitted
“
Serum”
B
D
C
Parenterally
transmitted
F- Mutant
Of B
GSlide6
Type of Hepatitis
A
B
C
D
E
Source of
virus
Feces
Blood
Blood derived
Body fluids
Blood
Blood derived
Body fluids
Blood
Blood derived
Body fluids
Feces
Route of
Transmission
Feco-oral
Percutaneous
Permucosal
Percutaneous
Permucosal
Percutaneous
Permucosal
Feco-oral
Chronic
Infection
No
Yes
Yes
Yes
No
PreventionPre PostExposureImmunizationPre PostExposureImmunizationBlood donor screeningBlood donor screeningPre PostExposureImmunizationEnsureSafe Drinkingwater
6Slide7
7
Hepatitis B VirusSlide8
4
、
Epidemiology
350,000,000 carriers worldwide120,000,000 carriers in China
- the carrier rate can exceed 10%
-15 to 25% of chronically infected patients will die from chronic liver disease
500,000 deaths/year in China
50% of children born
from
mothers with chronic HBV in the US are Asian American
8Slide9
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - LowSlide10
Whom to screen
Patients with elevated liver enzymes
Patients with HCC, Cirrhosis ,liver fibrosis
Immigrants from areas of high HBV prevalence
Families , household members and sexual contacts of HBV + person
Patients in psychiatric institutions, residents of welfare institutions and mentally disabled
Homo/Bisexuals and person having multiple sexual partners
Active and ex drug user
Dialysis patients Slide11
11
Parenteral
-
IV drug abusers
,
h
ealth
w
orkers are at increased risk.
Sexual
- sex workers and homosexuals are particular at risk.
Perinatal (
Vertical)
–
mother
(
HBeAg
+)
→
infant
.
HBV
:
Modes of TransmissionSlide12
Properties of HBV
a member of the
hepadnavirus
groupCircular partially
double-stranded DNA
viruses
Replication involves a
reverse transcriptase.
12Slide13
HBV
: Structure
Virion
also referred to as
Dane particle (
d
-
stranded DNA)
42nm enveloped virus Core antigens located in the center (nucleocapsid) * Core antigen (
HBcAg) * e antigen (HBeAg)- an indicator of transmissibility (minor component of the core- antigenically distinct from HBcAg) 22nm spheres and filaments other forms- no DNA in these forms so they are not infectious (composed of surface antigen)- these forms outnumber the actual virions
13Slide14
HBV
Structure &
Antigens
14
Dane particle
HBsAg
= surface (coat) protein (
4 phenotypes : adw, adr, ayw and ayr)
HBcAg
= inner core protein (
a single serotype)
HBeAg
= secreted protein; function unknownSlide15
Serology
Antigen Detection-
HBsAg,HBcAg,HBeAg
Antibody Detection-Anti HBc, Anti-HBe, Anti-HBsDNA Detection- HBV DNASlide16
DiagnosisSlide17
Clinical Features
Incubation period: Average 60-90 days
Range 45-180 days
Insidious onset of symptoms.
Tends to cause a more severe disease than Hepatitis A.
Clinical illness (jaundice): <5
yrs
, <10%
≥ 5
yrs, 30%-50% 1/3 adults-no symptoms
Clinical Illness at presentation 10 - 15%Acute case-fatality rate: 0.5%-1% Chronic infection: < 5 yrs, 30%-90% ≥ 5 yrs, 2%-10%
More likely in asymptomatic
infections
Premature mortality from
chronic liver disease:
15%-25%Slide18
Hepatitis B
-Signs
and SymptomsNauseaLoss of appetite
Vomiting
Fatigue
Fever
Dark urine
Pale stool
JaundiceStomach painSide painItchy skinHepatitis B virus has been linked to the development of Membranous
glomerulonephritis (MGN).Slide19
Diagnosis
A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection.
HBsAg
- used as a general marker of infection.
HBsAb
- used to document recovery and/or immunity to HBV infection.
anti-
HBc
IgM
- marker of acute infection.
anti-
HBcIgG
- past or chronic infection.
HBeAg
- indicates active replication of virus and therefore infectiveness.
Anti-
Hbe
- virus no longer replicating. However, the patient can still be positive for
HBsAg which is made by integrated HBV.HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.Slide20
HBsAg negative
antiHBc negative susceptible
antiHBs negative
HBsAg negative
antiHBc positive immune due to natural infection
antiHBs positive
HBsAg negative
antiHBc negative immune due to vaccine
antiHBs positive
HBsAg positive
antiHBc ( total ) positive acutely infected
IgM antiHBc positive
antiHBs negative
HBsAg positive
antiHBc
(
IgG
)
positive chronicallyIgM antiHBc negative infectedantiHBs negative
HBsAg negative antiHBc ( IgG) positive antiHBs negative
Interpretation of Hepatitis B Panel
1.resolution of chronic infection
2. “window period” infection3. false-positive anti-HBc4. active infection with waning HBsAgSlide21
Differential diagnosis
-
Acute icteric hepatitis
The jaundice caused by another diseaseHemolytic jaundice Extrahepatic obstructive jaundice
Hepatitis caused by another reasons
Toxic hepatitis
Infective toxic hepatitis
Mononucleosis
Alcohol hepatic disease
Schistosomiosis Wilson disease Slide22
Phases of Chronic HBV InfectionSlide23
Immune tolerant
HBsAg
and HBeAg detectable Biopsy
not
generally
indicatedHBV DNA >20,000 IU/mL (>105 copies/mL) Antiviral therapies are generally ineffectiveALT normal Risk of drug resistance
if treated with nucleos(t)ide analogsAbsent or minimal liver inflammation and fibrosis Continued monitoring recommendedSlide24
HBeAg+
immune active
HBsAg and
HBeAg
remain detectable Most children still show no signs or symptoms of disease
HBV DNA >20,000 IU/mL (>105 copies/mL) Biopsy indicated
ALT persistently
elevated
:
Appropriate testing should be considered to rule out other liver diseasesLiver infl
ammation
and
fi
brosis
can develop Treatment should be
consideredSlide25
Inactive
HBsAg
‘‘carrier’’
HBsAg
present
Age
at seroconversion appears to be influenced
by
HBV
genotype
HBeAg
undetectable, anti-HBe present . Risk
of developing
cirrhosis declinesHBV DNA <2000 IU/mL
(<104 copies/mL
)or undetectable . Risk of developing HCCALT normal . Biopsy
generally not indicatedAbsent or minimal liver inflammation, fibrosis
will regress
over time. Continued monitoring recommendedSlide26
Reactivation or
HBeAg-negative
immune
activeHBsAg
present
o
ccurs
in 20-30% of patientsHBeAg
remains negative and anti-HBe positive Called
‘‘
e-antigen-negative
’’
hepatitis
B
HBV DNA
levels >2000 IU/mL (>104 copies/mL) Usually
due to
basal core promoter or
precore mutation
ALT normal or elevated Liver biopsy indicated, especially if
ALT abnormalActive liver inflammation and fibrosis :Treatment should
be considered
if moderate or severe inflammation or fibrosis present.Treatment with nucleos(t)ide
analogs may be long-termSlide27
Possible Outcomes of HBV Infection
Acute
hepatitis B infection
Chronic HBV infection
3-5% of adult-acquired
infections
95% of infant-acquired infections
Cirrhosis
Chronic hepatitis
12-25% in 5 years
Liver failure
Hepatocellular
carcinoma
Liver transplant
6-15% in 5 years
20-23% in 5 years
Death
DeathSlide28
A liver biopsy is indicated in the following scenarios
:
HBeAg-negative and HBV DNA ≥ 20,000 IU/ml and ALT < 2x ULN
HBeAg
-negative
and HBV DNA = 2,000–19,999 IU/ml
HBeAg-positive and HBV DNA ≥ 20,000 IU/ml and ALT < 2x ULN and age ≥ 40Slide29
Treatment Slide30
Goals of HBV Therapy
HBV infection cannot eliminated or “cured”
The clinical goal of HBV treatment (primary goal )
Prevention or reversal of complications /deaths suppress HBV replication and achieve a target HBV DNA <10-15 IU/
mL
Can allow biochemical remission and prevent further liver injurySlide31
Goals of HBV Therapy
In
HBeAg
-positive patients (cont)HBeAg loss and
seroconversion
In
HBeAg
-positive and
HBeAg
-negative patients HBsAg loss and seroconversion is ultimate form of HBV treatment success Best predictor of durable viral suppression Strongest indicator of best longterm outcome, lowest risk of cirrhosis and liver cancerNot achieved by the majority of patients
Histological Improvement Slide32
Options in treatmentSlide33
Interferon alfa-2b
Lamivudine
Adefovir
Peginterferon alfa-2a
Telbivudine
Tenofovir
1990
1998
2002
2005
2006
2008
Entecavir
1990
1998
2002
2005
2006
2008
Evolution of Approved HBV Therapy Over TimeSlide34
Treatment
Interferon
- for
HBeAg
+
ve
carriers with chronic active hepatitis. Response rate is 30 to 40%.
alpha-interferon 2b (original)
alpha-interferon 2a (newer, claims to be more efficacious and efficient)
Lamivudine
- a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.
Adefovir
– less likely to develop resistance than
Lamivudine
and may be used to treat
Lamivudine
resistance HBV. However more expensive and toxic
Entecavir
–
most powerful antiviral known, similar to
AdefovirSuccessful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.Slide35
I
nterferon
-Alfa
IFN-alfa-2b
has been used for the treatment
of
chronic
HBV infection in children for more than a decade.
Lamivudine is now considered first-line therapy. Lamivudine is labeled for treatment of
chronic HBV infection in children of age 3
and
older
.
Discontinue lamivudine only when repeated assays demonstrate HBeAg loss or seroconversion to HBeAb
Adefovir Dipivoxil
. Adefovir is labeled for use in children age 12 years and older, and is the
preferred oral
treatment option for children ages 12-15Entecavir and Tenofovir -
adolescentSlide36
Prevention
Vaccination
- highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries.
Hepatitis B Immunoglobulin
- HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive.
Other measures
- screening of blood donors, blood and body fluid precautions.Slide37
Hepatitis B Vaccine
Infants: several options that depend on status of the mother
If mother HBsAg negative: birth, 1-2m,6-18m
If mother HBsAg positive: vaccine and Hep B immune globulin within 12 hours of birth, 1-2m, <6m
Adults
* 0,1, 6 months
Vaccine recommended in
All those aged 0-18
Those at high risk
37Slide38
AASLD 2007
[1]
US Algorithm 2008
[2]
EASL 2009
[3]
HBV DNA, IU/
mL
>
20,000
>
20,000
≥
2,000
ALT, x ULN*
> 2
> 1
> 1
Disease stage/grade
Moderate/severe
necroinflammation
and/or significant fibrosis
First-line therapy
ADV,
†
ETV,
pegIFN
ETV, TDF,
pegIFN
ETV, TDF,
pegIFN
Criteria for HBV DNA, ALT and disease stage/grade must all be met
If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease
1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3.
EASL HBV Guidelines. J Hepatology. 2009;50:227-242. Recommendations for Treatment Initiation in HBeAg-Positive Patients Slide39
AASLD 2007
[1]
US Algorithm 2008
[2]
EASL 2009
[3]
HBV DNA, IU/
mL
>
20,000
‡
> 2000
≥
2000
ALT, x ULN*
1 to > 2
> 1
> 1
Disease stage/grade
Moderate/severe necroinflammation
and/or significant fibrosis
First-line therapy
ADV,
†
ETV,
pegIFN
ETV, TDF,
pegIFN
ETV, TDF,
pegIFN
Criteria for HBV DNA, ALT and disease stage/grade must all be met
If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease
1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.
Recommendations for Treatment Initiation in HBeAg-Negative Patients Slide40
Selecting
an Interferon-Based Initial HBV TreatmentSlide41
Factors
Associated With Choosing Interferon for Initial Therapy
Favorable predictors of response
Genotype A or B > C or D
Low HBV DNA (baseline and on treatment)
High ALT (baseline)
Specific patient demographics
Younger people
Young woman wanting future pregnancy
Patient preferenceNo coinfection
with HIVConcomitant HCV infectionSlide42
Months
Depression
Fatigue
Flu-like symptoms
Anxiety
1
2
3
4
0
Increase in Incidence/Severity
Keeffe
EB, et al.
Clin
Gastroenterol
Hepatol
. 2008;6:1315-1341.
Patients should be carefully monitored for adverse events
Most common adverse events: flu-like symptoms (fever, chills, headache, malaise, and
myalgia
) as well as psychological impairment
PegIFN Treatment-Associated Adverse EffectsSlide43
On
interferon alpha therapy:
Primary non-response
is defined as less than 1 log10 IU/ml decrease in HBV DNA level frombaseline at 3 months of therapy.
Virological
response
is defined as an HBV DNA
concentration of less than 2000 IU/ml at 24 weeks
of therapy. Serological response is defined by HBe seroconversionin patients with HBeAg-positive CHB.Slide44
Slide45
Monitor HBV patients who are not in treatment
HBeAg
(+) and treatment not indicated
: ALT every 3–6 months if WNL; ALT every 1–3 months if 1–2x ULN. HBV DNA viral load every 6–12 months.
Liver biopsy if ALT ≥ 2x ULN for 6 months,
or if ALT 1–2x ULN for 6 months and
age ≥ 40
HBeAg
(–) and treatment not indicated
: ALT every 3 months for 1 year; then every 6–12 months. HBV DNA viral load if ALT > 1–2x ULN. Liver biopsy if persistent ALT elevation or HBV DNA ≥ 2,000 IU/ml.Slide46
.
Monitoring schedule for
Nucleos
(t)
ide
Analogues
:
ALT and AST levels every 3–6 months
HBeAg
every 3–6 months (in patients who are
HBeAg
(+) at start of treatment)
HBsAg
every 6–12 months (in patients who are
HBeAg
(–) at start of treatment) HBV DNA viral load every 3 months during first year of therapy; then every 6 months
Serum creatinine every 12 weeks while taking adefovir or tenofovirMonitoring schedule for Interferon alfa
:
Monitor patients on treatmentSlide47
Monitor
patients on treatment
Monitoring schedule for
Nucleos
(t)
ide
Analogues
:
ALT
and AST levels every 3–6 monthsHBeAg every 3–6 months (in patients who are HBeAg(+) at start of treatment)HBsAg every 6–12 months (in patients who are HBeAg(–) at start of treatment)
HBV DNA viral load every 3 months during first year of therapy; then every 6 monthsSerum creatinine every 12 weeks while taking adefovir or tenofovirMonitoring schedule for Interferon alfa:Slide48
Hepatitis CSlide49
HEPATITIS C VIRION: spherical, icosahedral,
NUCLEIC ACID: ss (+) RNASlide50
hypervariable
region
capsid
envelope
protein
protease/ helicase
RNA-dependent
RNA polymerase
c22
5’
core
E1
E2
NS2
NS3
33
c
NS4
c-100
NS5
3’
Hepatitis C VirusSlide51
Hepatitis C Virus
Genome
resembled that of a
flavivirus
positive stranded RNA genome of around 10,000
bases
1 single reading frame, structural genes at the 5' end, the non-structural genes at the 3' end.
enveloped virus,
virion
thought to 30-60nm in diameter
morphological
structure remains
unknown
HCV has been classified into a total of six genotypes (type 1 to 6) on the basis of phylogenetic
analysis
Genotype 1 and 4 has a poorer prognosis and response to interferon
therap
y
In Hong Kong, genotype 1 accounts for around 67% of cases and genotype 6 around 25%.Slide52
HCV replicates exclusively in the cytoplasm
via an RNA intermediate
Nucleus
Viral entry & uncoating
Translation & processing
(+)
(+)
(-)
(+)
HCV RNA
replication
Virus particle
assembly
Replicative
intermediateSlide53
Clinical Features of HCV Infection
in Children
Acute infection is rarely symptomatic
Chronic infection is rarely symptomaticchronic fatigue may be difficult to assessextrahepatic manifestations are much less common than in adultsSlide54
Incubation period:
Range 2-26
wks
Average
6-7 wks
Clinical illness (jaundice):
30-40% (20-30%)
Chronic hepatitis:
70%
Persistent infection:
85-100%
Immunity:
No protective antibody
response identified
Hepatitis
C - Clinical FeaturesSlide55
Hepatitis C
Nausea
Loss of appetite
VomitingFatigueFeverflu-like symptomsmuscle pain joint pain
Dark urine
Pale stool
Jaundice
Stomach pain
Side pain
cognitive changesdepression, headaches,
and mood swings.
Symptoms
3 out of 4 persons have no symptoms and can infect others without knowing itSlide56
Laboratory examination
Liver function
Serum
transaminase ALT(alanine transferase
)
↑
AST(
aspartase
transferase) ↑ALP (Alkaline phosphatase) ↑in chronic hepatitis LDH (Lactate
dehydrogenase) ↑Serum protein Albumin ↓In chronic hepatitis Ig ↑↑The ratio of A/G ↓
Bilirubin
Urobilinogen
↑
in early stage of AIHSlide57
Hepatitis A
Serologic
marker
Anti-
HAVIgM
: recent infection
Anti-
HAVIgG
: past infection
Marker of feces HAV particles may be detected by RIA or IEMIsolation of HAV may use tissue culture or animal inoculation Hepatitis BSero
-immunologic marker HBsAg anti-HBsHBcAg anti-HBcHBeAg anti-HbeMolecular biological marker DNApHBV DNAImmune tissue chemistry examination Detection of the markers of hepatitis virus:Slide58
Hepatitis
C
Serological
marker Anti-HCVIgMAnti-HCVIgG
Molecular biologic marker
HCV RNA may be detective by RT-PCR 1-2 weeks after infection of HCV
Quality of HCV RNA
Immune tissue chemistry method detect
HCAg
within liver cells Hepatitis DHDAg anti-HDVHDV RNAHepatitis E
Anti-HEVIgG,Anti-HEVIgmRT-PCRHEV particais: IF IEMSlide59
Hepatitis C
Long term pathogenesis
Over time progressive liver damage may occur
20 -30 % of those infected will develop cirrhosis over 10 - 30 years Of those with cirrhosis 25-30% (5% of overall) will develop end-stage liver disease or liver cancerMany live without symptoms for decadesOthers experience mild symptoms --intermittent fatigue, nausea, joint
,
muscle aches
,
skin
allergiesSlide60
60
Symptoms
anti-HCV
ALT
Normal
0
1
2
3
4
5
6
1
2
3
4
Hepatitis C Virus Infection
Typical Serologic Course
Titre
Months
Years
Time after ExposureSlide61
Because
HCV immunoglobulin G antibodies can cross the placenta, it is not useful to test neonates for potential mother-to-infant transmission until the infant is 18 months of age; at this time, the initial test should be for anti-HCV immunoglobulin G
If this test is positive, then HCV RNA levels should be measured. Screening for HCV should be considered for children born to mothers who have HCV or use intravenous drugs, children with human immunodeficiency virus, illicit drug users, patients with a history of incarceration or other high-risk behaviors, international adoptees or immigrants from high-prevalence areas (e.g., Africa and Asia), individuals with unexplained or prolonged serum transaminase elevations, and patients with needle stick injuries. Slide62
62
Laboratory Diagnosis
HCV antibody
- generally used to diagnose hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears.
HCV-RNA
- various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in monitoring the response to antiviral therapy.
HCV-antigen
- an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.Slide63
63
HCV RNA (PCR testing)
Virus load
Lower detection limit can be 10-615 IU/ml
NOT
a predictor of disease severity: a high viral
load does not mean the liver disease is more
severe, and a low viral load does not mean thepatient is ok and does not need therapy! Helps predict response rate to treatment (lowermeans a higher chance of cure with therapy) Used to monitor response during treatmentSlide64
64
Prognostic Tests
Genotyping – genotype 1 and 4 have a worse prognosis overall and respond poorly to interferon therapy. A number of commercial and in-house assays are available
.
Genotypic methods – DNA sequencing, PCR-hybridization e.g. INNO-LIPA.
Serotyping – particularly useful when the patient does not have detectable RNA.
Viral Load – patients with high viral load are thought to have a poorer prognosis. Viral load is also used for monitoring response to IFN therapy
.Slide65
TREATMENT
Although
adults with genotype 1 CHC have a range of treatment options, including direct-acting antivirals (DAAs), these drugs have not been approved for use in children, nor have they been tested in the pediatric population. Instead, the mainstay of treatment for children is the Food and Drug Administration approved combination of PEG-IFN and ribavirin (RBV).
At
the same time, the decision to treat children can still be challenging because the disease progresses slowly in childhood, serious complications from CHC are rare during childhood, and side effects from treatment are common
-Slide66
66
Treatment
CHILDREN
INTERFERON
–
.
The response rate is around 50% but 50% of responders will relapse upon withdrawal of treatment
.
RIBAVIRIN
a
combination of interferon and ribavirin is more effective than interferon alone
.
ADULTS
TELAPREVIR/BOCEPREVIR (
not
for naive
genotype
1), SOFOSBUVIR, SIMEPREVIR
NEW TREATMENTS INTERFERON-FREE Slide67
Recommendations
for
adults
Genotype
1
Recommended
regimen
for treatment-naive patients with HCV genotype 1 who are eligible to receive IFN.Daily sofosbuvir (400 mg) and weight-based
RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is recommended for IFN-eligible persons with HCV genotype 1 infection, regardless of subtype.Rating: Class I, Level ASofosbuvir
is
a
prodrug
of a
nucleotide
analogue inhibitor of the HCV NS5B RNA-dependent RNA polymerase. Slide68
Recommendations for adults
Recommended
regimen for treatment-naive
patients
with
HCV
genotype
1 who are not eligible to receive
IFN.Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [
>
75 kg] for 12
weeks
is
recommended for IFN-ineligible patients with HCV genotype 1 infection, regardless of subtype.Rating: Class I,
Level BSlide69
Recommendations for adults
Alternative
regimens
for treatment-naive patients with HCV genotype 1 who are
eligible
to
receive
IFN.Daily simeprevir (150 mg) for 12 weeks and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 24 weeks is an acceptable regimen for
IFN-eligible persons with eitherHCV genotype 1b orHCV genotype 1a infection in whom the Q80K polymorphism is not detected prior to treatment.
Rating:
Class
IIa
,
Level
ASlide70
Recommendations for adults
Alternative
regimens
for treatment-naive patients with HCV genotype 1 who are
not
eligible
to
receive IFN.Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is an acceptable regimen for IFN-ineligiblepersons
with HCV genotype 1 infection, regardless of subtype; however, preliminary data suggest that this regimen may be less effective than daily sofosbuvir (400 mg) plus
simeprevir
(150 mg),
particularly
among
patients with cirrhosis.Rating: Class IIb, Level BSlide71
Recommendations for adults
Recommended
regimen for treatment-naive patients with HCV genotype 2, regardless
of
eligibility
for IFN
therapy
:
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for treatment-naive patients with HCV genotype
2 infection.Rating: Class I, Level ASlide72
Recommendations for adults
Recommended
regimen for treatment-naive patients with HCV genotype 3, regardless
of
eligibility
for IFN
therapy
:
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for treatment-naive patients with HCV genotype
3 infection.Rating: Class I, Level BSlide73
Recommendations for adults
Alternative
regimens
for treatment-naive patients with genotype 3 who are
eligible
to
receive
IFN.Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is an acceptable regimen for IFN-eligible
persons with HCV genotype 3.Slide74
74
OUTCOMES of HCV hepatitisSlide75
75
Screening of blood, organ, tissue donors
High-risk behavior modification
Blood and body fluid precautions
Prevention of Hepatitis CSlide76
76
HEPATITIS D VIRUS
(HDV, DELTA AGENT)
VIRION: spherical, 36-38 nm,
HBV capsid, HDV nucleoprotein
NUCLEIC ACID: (-) ss RNA, circular
Satellite virus : replicates only
in the presence of HBVSlide77
77
Hepatitis D Virus
The delta agent is a defective virus which
shows similarities with the viroids in plants.
The agent consists of a particle 35 nm in diameter consisting of the delta antigen surrounded by an outer coat of HBsAg.
The genome of the virus is very small and consists of a single-stranded RNA Slide78
78
.
Coinfection
severe acute disease low
risk of chronic infection.
Superinfection
usually develop chronic HDV infection.
high risk of severe chronic liver disease.
may present as an acute hepatitis.
Hepatitis D - Clinical FeaturesSlide79
Consequences of hepatitis B and delta virus infection
Slide80
80
Percutaneous exposures
injecting drug
use
Permucosal
exposures
sex contact
Hepatitis D Virus Modes of TransmissionSlide81
CIRRHOSIS OF LIVERSlide82
Etiology of
child
’s
cirrhosisHepatitis B and
C
Autoimmune
hepatitis
Inherited
diseases:Glycogen storage diseaseTyrosinemiaWilson diseaseAlpha1-antitrypsin
deficiencyCystic fibrosisBile duct diseases:Biliary artresiaSclerosing cholangitisCongenital hepatic fibrosisCholedochal cysts
Drugs
and
toxins
:
IsoniazidMethotrexateExcess vitamin AFatty liver diseaseSlide83
Cirrhosis
Definition:
It is the end stage of liver disease characterized by
Bridging fibrous septa in the form of delicate bands or broad scar linking portal tracts with one another and portal tracts with terminal hepatic vein
Parenchymal nodules containing hepatocytes encircled by fibrosis
Disruption of architecture entire of liver
Slide84
Normal LiverSlide85
Normal Liver Histology
CV
PTSlide86
Histological classification
Micronodular
Cirrhosis
:Thick regular septa and regenerating small nodules varying little in size and involvement of every lobule, mainly seen in alcoholic cirrhosis.
Size of the nodule is less than 1cmSlide87
Histological classification
Micronodular Cirrhosis
Slide88
Histological classification
Macronodular Cirrhosis
:
Septa and nodules of variable size and normal lobules in larger nodules, mainly seen in post necrotic cirrhosis.
Size of the nodule is more than 1cmSlide89
Liver Biopsy – CirrhosisSlide90
Liver Biopsy – Cirrhosis:Slide91Slide92
Clinical Feature of cirrhosis
Signs:
Jaundice
Fetor
hepaticus
Pedal oedema
Generalized wasting
Hands:
Leuconychia
, clubbing, Jaundice, Flapping tremor,
palmar erythema, dupuytren’s contructure
Slide93
Clinical Feature of cirrhosis
Parotid enlargement
Loss of secondary sexual hair, axillary and pubic
Gynaecomastia in
boys
and breast atrophy in females.
Testicular atrophy in males.
skin: spider
naevi
in the upper limbs and chest, generalized pigmentation, purpura, bruisingSlide94
Clinical Feature of cirrhosis
Abdomen :
Dilated abdominal vessels, caput medusa
Ascitis
Splenomegaly
Hepatomegaly
Haemorrhoid
Ascites is suggested by the following findings on physical examination:
Abdominal distention
Bulging flanksShifting dullnessElicitation of a "puddle sign" in patients in the knee-elbow positionSlide95
Palmar
er
ythemaSlide96
Ascitis in CirrhosisSlide97
Porta
-systemic
anastomosis
: Prominent abdominal veins.Slide98
Splenomegaly in cirrhosisSlide99
Grade 0 - Subclinical
; normal
mental status but minimal changes in memory, concentration, intellectual function, coordination
Grade 1 - Mild confusion,
euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern (
ie
, inverted sleep cycle)
Grade 2 - Drowsiness,
lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent disorientation (usually with regard to
time)
Grade 3 - Somnolent, but arousable, state; inability to perform mental tasks; disorientation with regard to time and place; marked confusion; amnesia; occasional fits of rage; speech is present but incomprehensible
Grade
4 - Coma, with or without response to painful stimuliSlide100
Lab investigations
Liver function: serum albumin and prothrombin are the best indicator of liver functions.
Albumin is less than 28 g/l
Prothrombin time increase according to the severity of the disease
Serum bilirubin is elevated
Liver biochemistry: this can be normal depending on the severity of the cirrhosis
ALP is elevated
ALT is elevated
Slide101
Lab investigations
Serum electrolytes: A low sodium indicate severe disease due to defect in the free water clearance or excess diuretic therapy.
Serum Creatinine: An elevation concentration of more than 130micromol/l indicate worse prognosis
In addition Alpha feto protein more than 200ng/ml strongly suggest that
hepato
cellular carcinomaSlide102
Lab investigations
Other test to identify the cause
Viral marker :
HBsAg,Anti
HCV
Alpha-1
antitripsin
Serum copper,
Caeruloplasmin
Serum immunoglobulin
Auto antibodyIron indices,ferritin Slide103
Imaging
Ultrasonogram
examinition:Liver may show coarse ecotexture
Dilated portal veins
Splenomegaly
Ascitis
CT scan
may show
hepatosplenomegaly and dilated collaterals are seen in chronic liver diseaseUpper GI endoscopy: Oesophageal varices may seen Liver stiffness measurement in children using FibroScan LIVER BIOPSY IS CONFIRMATORY Slide104
Prognosis of Cirrhosis
Poor prognostic indicator of cirrhosis:
Blood tests low Serum albumin is( <28 g/l)
Low Sodium is (<125mmol/l)
Prolong
ed
prothrombin
time(> 6sec)Serum Creatinine is (> 130micromol/l)ClinicalPersistent jaundiceAscitisFailure of response to therapy
Hemorrhage from the varices, particularly with poor liver functionSlide105
Prognosis of Cirrhosis
Prognosis can be assessed by using
CHILD-PUGH
CLASSIFICATION
P
a
rameter
Ascitis
None
Mild
Moderate/ SevereEncephalopathyNone Mild MarkedBilirubin<2mg/dl2-3mg/dl>3mg/dl
Albumin
>3.5g/dl
2.8-3.5g/dl
<2.8g/dl
Prothrombin time
<4
4-6>6Slide106
Prognosis of Cirrhosis
Score
5-6 grade A (well-compensated disease)
Score 7-9 grade B
(Significant functional compromise)
Score 10-15 grade C
(Decompensated disease)Slide107
Complication of cirrhosis
Ascitis
Spontaneous bacterial peritonitis
Heamatemesis
Enc
e
phalopathy
Hepatocellular carcinoma
Hepato
renal syndrome Increased susceptibility of infection Slide108
TREATMENT
- acide
ursodesoxycholique
15 mg/kg/jourPrednisone and azathioprine - For
autoimmune
hepatitis
Interferon
and
other antiviral agents - For hepatitis B and CPhlebotomy - For hemochromatosisUrsodeoxycholic acid - For primary biliary cirrhosisTrientine and zinc - For Wilson disease
Liver transplantationSlide109
FULMINANT HEPATIC FAILURESlide110
Symptoms
Altered mental status and
coagulopathy
in the setting of acute hepatic diseaseFulminant considered <8 wks from jaundice to encephalopathy
Subfulminant
<26 weeks
Jaundice
Encephalopathy – stupor , coma
Decreased synthetic function with INR>1.5
New ascitesSlide111
Differential diagnosis
Vascular: Budd-
Chiari
(hepatic vein thrombosis), ischemia “shock liver”, hepatic veno-occlusive dz, portal vein thrombosis, arterial thrombosis
Infectious: Hepatitis A/B, HSV, CMV, EBV, Hemorrhagic fever viruses (
ebola
,
lhassa
,
marburg), paramyxoviruses. Toxoplasma, Leptospira, Candida, Brucella, MyobacteriaTrauma: lacerationAutoimmune/Inflam: Autoimmune hepatitis, Reye syndrome , onset Still’s dZ
Inherited/Cong: Wilson’s disease, hemachromatosis, alpha-1 antitrypsin def., galactosemia, tyrosinemia, urea cycle disorders (ornithine transcarbamylase def.), fructose intoleranceNeoplastic: Primary vs metastatic lesionsDrugs/toxinsSlide112
Differential: Drugs/Toxins
Acetaminophen
Alcohol (chronic use depletes glutathione stores)
Antidepressants: amitriptyline, nortriptylineOral hypoglycemics: roglitazone, troglitazoneAntiepileptics: phenytoin, valproateAntibiotics: tetracycline, amox/clav, cipro, doxy, erythromycin, isoniazid, nitrofurantoinSlide113
TOXINS
Anesthetic agents: halothane
Statins
Immunosuppressants: cyclophosphamide, methotrexateSalicylates: Reye syndromeGold
Disulfiram
PropylthiouracilSlide114
Toxins: continued…
Dose dependent toxin mediated
Bacillus cereus
toxin
Cyanobacteria toxin
Organic solvents (eg, carbon tetrachloride)
Yellow phosphorus (fireworks)
Amanita phalloides
mushroom toxin
Galerina
mushrooms Illicit DrugsEcstasyCocaineHerbal SupplementsGinseng Pennyroyal oil Teucrium polium Chaparral or germander tea Kava Kava (kawa kawa)Slide115
Epidemiology
Caucasian (72%) > Hispanic > African American> Asian
Toxin mediated #1 in US
Acetaminophen 42%
Idiosyncratic drug 12%
Hepatitis B
Autoimmune hepatitis
Wilson’s disease
Fatty liver
dz of pregnancy, HELLPWorldwideHBV +/- HDVHEV (particularly in pregnant women in Mexico, Central America, India, SE Asia)
Acetaminophen in Europe, Great BritainSlide116
Pathology
Panlobular
necrosis common in medication related and virally mediated disease
Centrilobular necrosis extending along the portal tracts common in acetaminophen toxicityMicrovesicular steatosis suggests valproate or salicylates as primary injury or acute fatty liver of pregnancySlide117
Laboratory Studies
Capillary glucose
Ammonia
Chemistry Liver panel w/albuminLipaseCoags (INR >1.5)Type & screenCBC LactatePregnancy test
Acetaminophen &
salicylate
level
Toxicology screen
Viral
serologies: anti- HAV IgM HBV surf ag/ab, core IgMHEVANA, ASMA, LKMA, Ig levels
Ceruloplasmin (acute phase rxct)Serum free copperHIVBlood culturesSlide118
Radiology
CT Head: cerebral edema, mass lesions
Liver u/s with
dopplers: eval clot, parenchymaLiver CT vs MRI: delineate anatomy for possible transplantationEEG: seizuresSlide119
Complications
Coagulopathy
Encephalopathy
Cerebral edema and herniationHypoglycemiaRenal failureSystemic Inflammatory Response Syndrome (SIRS) low SVRSepsisSlide120
Cerebral Edema
Vasogenic
and
cytotoxic in originAmmoniaglutamine which accumulates in cortical astrocytes
Increased cerebral blood flow via
NO2
TNF alpha
IL6 IL2 bacterial endotoxinSlide121
Initial management
Labs as indicated
Triage to appropriate service: consider ICU when grade II encephalopathy is present
for freq neuro checksN-acetylcysteineIntubation if GCS <8, grade III encephalopathy
Use short-acting , low dose meds only
Head CTSlide122
Encephalopathy
Grade
I
Confused, altered moodGrade II: Inappropriate, drowsyGrade 3: stuporous but
arousable
, markedly confused
Grade 4:
Coma, unresponsive to painSlide123
Mangement
: Antidotes
N-
acetylcysteineLoad 140mg/kg, then 15mg/kg/hr Pharmacy infusion protocol (call them!)Slide124
Management: Antidotes
Amanita = Penicillin G (mech unknown) 1mg/kg/d +/- activated charcoal
Silibinin – derivative of milk thistle, antioxidant (proposed but not well studied)
Inchinko-to – Chinese herbal preparation for cholestatic hepatitis (proposed suppression of TNF-α, inhibition of hepatic apotosis)Slide125
Management: Coagulopathy
Correction of coagulopathy not indicated unless active bleeding is present or procedure
FFP
( fresh frozen plasma) 15ml/kg or 4 unitscryoprecipitateFactor
VIIa
for unresponsive bleeding 4mcg/kg push
Platelet transfusion only <10K or procedure <50KSlide126
Management: Renal Failure
1/3 of patients will develop
oliguric
ARFFluid resusciationCVVHD (Continuous veno-venous hemodialysis
)
as indicated
Avoid nephrotoxic medications
Avoid NSAIDSSlide127
Management: CV and Endocrine
Fluid resuscitation
Low SVR with normal or increased CO
Dopamine or norepinephrine prnImpaired gluconeogenesisFrequent capillary blood glucose q1/2 D5/10 containing solution as necessaryMontior potassium, phosphate and magnesiumSlide128
Management: Antibiotics
Empiric antibiotics for
Progressive encephalopathy
Signs of SIRS (temperature, >38ºC or <36ºC; white blood cell [WBC] count, >12,000/μL or <4000/μL; pulse rate, >90 bpm) Persistent hypotensionZosyn
(
Piperacillin
/
tazobactam
)
and fluconazole considered initially. In hospital-acquired IV catheter infections, consider vancomycin.Slide129
Management: Cerebral edema
Lactulose
via NG to decrease ammonia
Mechanical ventilation to protect airway and hyperventilate (short-lived)Head of bed elevated to 30 degrees
Mannitol
(0.5 - 1g/kg) goal
osm
around 320
Hypertonic saline 3% ( goal
na 145-155)Barbituate comaHypothermia is under investigationSeizure control with phenytoinCall neurology/neurosurgery
earlyRefractory increased ICP or decreased CPP is a contra-indication for transplantation in most centersSlide130
Prognosis: King’s College Criteria
Acetaminophen toxicity
Arterial lactate >3.5 4 hrs after resuscitation
orpH <7.30 or lactate >3.0 12 hours after resuscit. orArterial pH <7.3PT >100 secCreatinine >3.4Slide131
Non-acetaminophen related toxicity
INR >6.5 (PTT>100)
or
Arterial lactate >3.5 4hrs after resuscitation or 3 of 5
Age <10 or >40
INR >3.5
Idiosyncratic drug
rxn
Jaundice > 1wk
Serum bilirubin >17.5mg/dLSlide132
MELD
Model for End-Stage Liver Disease
3
.78[Ln serum bilirubin (mg/dL)] + 11.2[
Ln
INR] + 9.57[
Ln
serum
creatinine
(mg/dL)] + 6.43Utilized to prioritize transplant recipientsIn hospitalized patients, the 3 month mortality is:40 or more — 100% mortality 30–39 — 83% mortality 20–29 — 76% mortality
10–19 — 27% mortality <10 — 4% mortality Slide133
METAVIR score
Portal
(piecemeal necrosis) Lobular activity ACTIVITY GRADE **0
none
none
or mild
A0: no PN or lobular activityfocal PN, some tracts at least 1 focus per lobule A1: mild PN (grade 1) diffuse PN some tracts OR multiple foci per lobule OR A2
: moderate PN (grade2) focal PN all tracts bridging necrosis OR lobular grade 23 diffuse PN all tracts A3
: PN grade 2 & lobular gr 2
OR
severe PN (grade 3)
Fibrosis
F0 no fibrosis F1 portal fibrosis without septa F2 portal fibrosis with rare septa F3 numerous septa without cirrhosis F4 cirrhosis Slide134
C.
Ishak
(
modified Knodell) scoreNecroinflammatory score A 0-4 Periportal or
periseptal
interface
hepatitis
(piecemeal necrosis) B 0-6 Confluent necrosis C 0-4 Focal (spotty) lytic necrosis, apoptosis, focal inflammation D 0-4 Portal inflammation Fibrosis
stage 0 No fibrosis 1 fibrous expansion of some portal areas (with or without spurs) 2 fibrous expansion of most portal areas (with or without spurs)
3
fibrous
expansion
of
most
portal areas with occasional portal-portal linkage 4 fibrous expansion of portal areas with marked portal-portal and some portal-central linkage 5 marked bridging (P-P and P-C) with occasional nodules (incomplete cirrhosis) 6 cirrhosis Slide135
Management: Transplant
Prior to orthotopic txplt, mortality >80%
6% of OLT due to fulminant hepatic failure
Mortality now around 20-40% center dependentCALL THE TRANSPLANT TEAM TO DISCUSS THE CASESlide136
REMEMBER:
Fulminant
hepatic failure is incredibly deadly so triage and treat aggressively
Get other smart people involved quicklyDon’t forget about metabolic disorders causing elevated ammonia levels (urea cycle)
Look for other causes when the patient doesn’t fit with expected course
History
Review
History
Think