CRONIC HEPATITIS, CIRRHOSIS,
HEPATIC FAILURE
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
2
Hepatitis Terms
• Acute Hepatitis: Short-term hepatitis.
– Body’s immune system clears the virus from
the body within 6 months
• Chronic Hepatitis: Long-term hepatitis.
– Infection lasts longer than 6 months
because the body’s immune system cannot
clear the virus from the body
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)
4
Viral Hepatitis - Historical Perspectives
“Infectious”
A
Viral hepatitis
“Serum”
Enterically
transmitted
E
NA:NB
D
C
F- Mutant
Of B
G
B
Parenterally
transmitted
5
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
Fecooral
Chronic
Infection
No
Yes
Yes
Yes
No
Prevention
Pre Post
Exposure
Immunization
Pre Post
Exposure
Immunization
Blood donor
screening
Blood donor
screening
Pre Post
Exposure
Immunization
Ensure
Safe
Drinking
water
6
Hepatitis B Virus
7
4、Epidemiology
• 350,000,000 carriers worldwide
• 120,000,000 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
8
Geographic Distribution of Chronic
HBV Infection
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low
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
HBV: Modes of Transmission
 Parenteral - IV drug abusers, health workers are
at increased risk.
 Sexual - sex workers and homosexuals are
particular at risk.
 Perinatal (Vertical) –mother
(HBeAg+)→infant.
11
Properties of HBV
• a member of the hepadnavirus group
• Circular partially double-stranded DNA viruses
• Replication involves a reverse transcriptase.
12
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
13
HBV Structure & Antigens
Dane particle
HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype)
HBeAg = secreted protein; function unknown
14
Serology
• Antigen Detection- HBsAg,HBcAg,HBeAg
• Antibody Detection-Anti HBc, Anti-HBe, AntiHBs
• DNA Detection- HBV DNA
Diagnosis
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:
Chronic infection:
0.5%-1%
< 5 yrs, 30%-90%
≥ 5 yrs, 2%-10%
More likely in asymptomatic infections
Premature mortality from
chronic liver disease:
15%-25%
Hepatitis B-Signs and Symptoms
– Nausea
– Loss of appetite
– Vomiting
– Fatigue
– Fever
– Dark urine
– Pale stool
– Jaundice
– Stomach pain
– Side pain
– Itchy skin
– Hepatitis B virus has
been linked to the
development of
Membranous
glomerulonephritis
(MGN).
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.
Interpretation of Hepatitis B Panel
HBsAg
antiHBc
antiHBs
HBsAg
antiHBc
antiHBs
HBsAg negative
antiHBc
positive
positive
antiHBs
HBsAg
antiHBc ( total )
IgM antiHBc
antiHBs
HBsAg
antiHBc ( IgG)
IgM antiHBc
antiHBs
HBsAg
antiHBc ( IgG)
antiHBs
negative
negative
positive
positive
positive
positive
negative
positive
positive
negative
negative
negative
positive
negative
negative
negative
susceptible
immune due
to natural infection
negative
immune due to vaccine
acutely infected
chronically
infected
1.resolution of chronic infection
2. “window period” infection
3. false-positive anti-HBc
4. active infection with waning HBsAg
Differential diagnosis
• - Acute icteric hepatitis
– The jaundice caused by another disease
• Hemolytic jaundice
• Extrahepatic obstructive jaundice
– Hepatitis caused by another reasons
• Toxic hepatitis
• Infective toxic hepatitis
• Mononucleosis
• Alcohol hepatic disease
• Schistosomiosis
• Wilson disease
Phases of Chronic HBV Infection
Immune tolerant
•
•
•
•
•
HBsAg and HBeAg detectable
Biopsy not generally indicated
HBV DNA >20,000 IU/mL (>105 copies/mL)
Antiviral therapies are generally ineffective
ALT normal Risk of drug resistance if treated with
nucleos(t)ide analogs
• Absent or minimal liver inflammation and fibrosis
• Continued monitoring recommended
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 diseases
• Liver inflammation and fibrosis can develop
Treatment should be considered
Inactive HBsAg ‘‘carrier’’
•
•
•
•
•
•
•
HBsAg present
Age at seroconversion appears to be influenced by HBV
genotype
HBeAg undetectable, anti-HBe present . Risk of
developing cirrhosis declines
HBV DNA <2000 IU/mL (<104 copies/mL)
or undetectable . Risk of developing HCC
ALT normal . Biopsy generally not indicated
Absent or minimal liver inflammation, fibrosis will
regress over time. Continued monitoring recommended
Reactivation or HBeAg-negative
immune active
• HBsAg present occurs in 20-30% of patients
• HBeAg remains negative and anti-HBe positive Called ‘‘eantigen-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 abnormal
• Active liver inflammation and fibrosis :Treatment should be
considered if moderate or severe inflammation or fibrosis
present.Treatment with nucleos(t)ide analogs may be longterm
Possible Outcomes of HBV Infection
Acute hepatitis B infection
3-5% of adultacquired infections
95% of infantacquired infections
Chronic HBV infection
Chronic hepatitis
12-25% in 5 years
6-15% in 5 years
Cirrhosis
Hepatocellular
carcinoma
Death
20-23% in 5 years
Liver failure
Liver transplant
Death
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 ≥ 40
Treatment
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 injury
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 cancer
Not achieved by the majority of patients
Histological Improvement
Options in treatment
Evolution of Approved HBV Therapy
Over Time
Peginterferon alfa-2a
Entecavir
Lamivudine
1990
1990
Interferon alfa-2b
1998
1998
2002
Adefovir
2005
2005
Tenofovir
2006
Telbivudine
2008
2008
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 Adefovir
• Successful response to treatment will result in the
disappearance of HBsAg, HBV-DNA, and seroconversion to
HBeAg.
• Interferon-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 12-15
• Entecavir and Tenofovir - adolescent
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.
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
37
Recommendations for Treatment
Initiation in HBeAg-Positive Patients
HBV DNA, IU/mL
ALT, x ULN*
Disease stage/grade
First-line therapy
AASLD 2007[1]
US Algorithm 2008[2]
EASL 2009[3]
> 20,000
> 20,000
≥ 2,000
>2
>1
>1
Moderate/severe necroinflammation
and/or significant fibrosis
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-Negative Patients
HBV DNA, IU/mL
ALT, x ULN*
Disease stage/grade
First-line therapy
AASLD 2007[1]
US Algorithm 2008[2]
EASL 2009[3]
> 20,000‡
> 2000
≥ 2000
1 to > 2
>1
>1
Moderate/severe necroinflammation
and/or significant fibrosis
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.
Selecting an Interferon-Based
Initial HBV Treatment
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 preference
No coinfection with HIV
Concomitant HCV infection
PegIFN Treatment-Associated
Adverse Effects
Increase in
Incidence/Severity
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
Depression
Fatigue
Anxiety
Flu-like
symptoms
0
1
2
Months
3
4
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
On interferon alpha therapy:
• Primary non-response is defined as
• less than 1 log10 IU/ml decrease in HBV DNA level from
• baseline 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 seroconversion
in patients with HBeAg-positive CHB.
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.
Monitor patients on treatment
.
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 tenofovir
Monitoring schedule for Interferon alfa:
Monitor patients on treatment
• 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 tenofovir
• Monitoring schedule for Interferon alfa:
Hepatitis C
HEPATITIS C VIRION: spherical, icosahedral,
NUCLEIC ACID: ss (+) RNA
Hepatitis C Virus
capsid
envelope
protein
protease/ helicase
c22
33c
RNA-dependentRNA polymerase
c-100
5’
3’
cor E1
e
E2
hypervariable
region
NS
2
NS
3
NS
4
NS
5
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 nonstructural 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 therapy
In Hong Kong, genotype 1 accounts for around 67% of cases
and genotype 6 around 25%.
HCV replicates exclusively in the cytoplasm
via an RNA intermediate
Viral entry & uncoating
(+)
Translation & processing
(+)
Virus particle
assembly
HCV RNA
replication
(-)
Replicative
intermediate
(+)
Nucleus
Clinical Features of HCV Infection
in Children
• Acute infection is rarely symptomatic
• Chronic infection is rarely symptomatic
– chronic fatigue may be difficult to assess
– extrahepatic manifestations are much less
common than in adults
Hepatitis C - Clinical Features
Incubation period:
Range 2-26 wks
Clinical illness (jaundice):
30%)
Average 6-7 wks
30-40% (20-
Chronic hepatitis:
70%
Persistent infection:
85-100%
Immunity:
No protective
antibody
response
identified
– Dark urine
Hepatitis–CPale stool
• Symptoms
– Jaundice
– Nausea
– Stomach pain
– Loss of appetite
– Side pain
– Vomiting
– cognitive changes
– Fatigue
– depression,
– Fever
– headaches,
– flu-like symptoms
– and mood swings.
– muscle pain
– joint pain
3 out of 4 persons have no symptoms and can
infect others without knowing it
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
• The ratio of A/G ↓
Ig ↑↑
 Bilirubin
• Urobilinogen ↑in early stage of AIH
Detection of the markers of hepatitis virus:
Hepatitis A
• Serologic marker
– Anti-HAVIgM: recent
infection
– Anti-HAVIgG: past
infection
• Marker of feces
– HAV particles may be
detected by RIA or
IEM
– Isolation of HAV may
use tissue culture or
animal inoculation
Hepatitis B
• Sero-immunologic marker
– HBsAg
– HBcAg
– HBeAg
anti-HBs
anti-HBc
anti-Hbe
• Molecular biological marker
– DNAp
– HBV DNA
– Immune tissue chemistry
examination
Hepatitis C
• Serological marker
– Anti-HCVIgM
– Anti-HCVIgG
Hepatitis D
• HDAg anti-HDV
• HDV RNA
• 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 E
• Anti-HEVIgG,Anti-HEVIgm
• RT-PCR
• HEV particais: IF IEM
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 cancer
– Many live without symptoms for decades
– Others experience mild symptoms --intermittent
fatigue, nausea, joint, muscle aches, skin allergies
Hepatitis C Virus Infection
Typical Serologic Course
anti-HCV
Symptoms
Titre
ALT
Normal
0
1
2
3
4
Months
5
6
1
2
3
Years
Time after Exposure
4
60
•
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 highprevalence areas (e.g., Africa and Asia), individuals with
unexplained or prolonged serum transaminase elevations,
and patients with needle stick injuries.
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.
62
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 the
patient is ok and does not need therapy!
Helps predict response rate to treatment (lower
means a higher chance of cure with therapy)
􀂄 Used to monitor response during treatment
63
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, PCRhybridization 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.
64
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 -
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
66
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 IFNeligible persons with HCV genotype 1 infection, regardless of subtype.
• Rating: Class I, Level A
• Sofosbuvir is a prodrug of a nucleotide analogue inhibitor of the HCV NS5B
RNA-dependent RNA polymerase.
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 IFNineligible patients with HCV genotype 1 infection,
regardless of subtype.
• Rating: Class I, Level B
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 either
• HCV genotype 1b or
• HCV genotype 1a infection in whom the Q80K polymorphism
is not detected prior to treatment.
• Rating: Class IIa, Level A
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 B
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 treatmentnaive patients with HCV genotype 2 infection.
• Rating: Class I, Level A
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 treatmentnaive patients with HCV genotype 3 infection.
• Rating: Class I, Level B
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 IFNeligible persons with HCV genotype 3.
OUTCOMES of HCV hepatitis
74
Prevention of Hepatitis C
 Screening of blood, organ, tissue donors
 High-risk behavior modification
 Blood and body fluid precautions
75
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 HBV
76
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
77
Hepatitis D - Clinical Features
–.
– 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.
78
Consequences of hepatitis B and delta virus
infection
Hepatitis D Virus Modes of
Transmission
 Percutaneous exposures
 injecting drug use
 Permucosal exposures
 sex contact
80
CIRRHOSIS OF LIVER
Etiology of child’s cirrhosis
• Hepatitis B and C
• Autoimmune hepatitis
• Inherited diseases:
– Glycogen storage disease
– Tyrosinemia
– Wilson disease
– Alpha1-antitrypsin
deficiency
– Cystic fibrosis
• Bile duct diseases:
– Biliary artresia
– Sclerosing cholangitis
– Congenital hepatic fibrosis
– Choledochal cysts
• Drugs and toxins:
– Isoniazid
– Methotrexate
– Excess vitamin A
• Fatty liver disease
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
Normal Liver
Normal Liver Histology
CV
PT
• 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 1cm
Histological classification
Micronodular Cirrhosis
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 1cm
Liver Biopsy – Cirrhosis
Liver Biopsy – Cirrhosis:
Clinical Feature of cirrhosis
Signs:
Jaundice
Fetor hepaticus
Pedal oedema
Generalized wasting
Hands: Leuconychia, clubbing, Jaundice, Flapping tremor,
palmar erythema, dupuytren’s contructure
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, bruising
Clinical Feature of cirrhosis
• Ascites is suggested by
the following findings
on physical
 Abdomen :
examination:
• Abdominal distention
 Dilated abdominal vessels, caput medusa• Bulging flanks
• Shifting dullness
• Elicitation of a "puddle
 Ascitis
sign" in patients in the
knee-elbow position
 Splenomegaly
 Hepatomegaly
 Haemorrhoid
Palmar erythema
Ascitis in Cirrhosis
Porta-systemic anastomosis:
Prominent abdominal veins.
Splenomegaly in cirrhosis
Grade 0 - Subclinical; normal mental
status but minimal changes in memory, Grade 3 - Somnolent, but arousable,
concentration, intellectual function,
state; inability to perform mental tasks;
coordination
disorientation with regard to time and
Grade 1 - Mild confusion, euphoria or place; marked confusion; amnesia;
depression, decreased attention,
occasional fits of rage; speech is present
slowing of ability to perform mental
but incomprehensible
tasks, irritability, disorder of sleep
Grade 4 - Coma, with or without
pattern (ie, inverted sleep cycle)
response to painful stimuli
Grade 2 - Drowsiness, lethargy, gross
deficits in ability to perform mental
tasks, obvious personality changes,
inappropriate behavior, intermittent
disorientation (usually with regard to
time)
Lab investigations
Liver function: serum albumin and prothrombin are
the best indicator of liver functions.
o Albumin is less than 28 g/l
oProthrombin time increase according to the
severity of the disease
oSerum bilirubin is elevated
Liver biochemistry: this can be normal depending on
the severity of the cirrhosis
oALP is elevated
oALT is elevated
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 carcinoma
Lab investigations
 Other test to identify the cause
Viral marker : HBsAg,Anti HCV
Alpha-1 antitripsin
Serum copper, Caeruloplasmin
Serum immunoglobulin
Auto antibody
Iron indices,ferritin
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 disease
• Upper GI endoscopy: Oesophageal varices may seen
• Liver stiffness measurement in children using FibroScan
•
LIVER BIOPSY IS CONFIRMATORY
Prognosis of Cirrhosis
Poor prognostic indicator of cirrhosis:
Blood tests
 low Serum albumin is( <28 g/l)
 Low Sodium is (<125mmol/l)
 Prolonged prothrombin time(> 6sec)
 Serum Creatinine is (> 130micromol/l)
Clinical
 Persistent jaundice
 Ascitis
 Failure of response to therapy
 Hemorrhage from the varices, particularly with poor liver function
Parameter
Ascitis
•
Prognosis of Cirrhosis
None be assessedMild
Moderate/ Severe
Prognosis can
by using CHILD-PUGH
CLASSIFICATION
Encephalopathy
None
Mild
Marked
Bilirubin
<2mg/dl
2-3mg/dl
>3mg/dl
Albumin
>3.5g/dl
2.8-3.5g/dl
<2.8g/dl
Prothrombin time
<4
4-6
>6
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)
Complication of cirrhosis
1.
2.
3.
4.
5.
6.
7.
Ascitis
Spontaneous bacterial peritonitis
Heamatemesis
Encephalopathy
Hepatocellular carcinoma
Hepato renal syndrome
Increased susceptibility of infection
TREATMENT
- acide ursodesoxycholique 15 mg/kg/jour
• Prednisone and azathioprine - For autoimmune
hepatitis
• Interferon and other antiviral agents - For hepatitis B
and C
• Phlebotomy - For hemochromatosis
• Ursodeoxycholic acid - For primary biliary cirrhosis
• Trientine and zinc - For Wilson disease
• Liver transplantation
FULMINANT HEPATIC FAILURE
Symptoms
• Altered mental status and coagulopathy in the
setting of acute hepatic disease
• Fulminant considered <8 wks from jaundice to
encephalopathy
• Subfulminant <26 weeks
• Jaundice
• Encephalopathy – stupor , coma
• Decreased synthetic function with INR>1.5
• New ascites
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, Myobacteria
• Trauma: laceration
• Autoimmune/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 intolerance
• Neoplastic: Primary vs metastatic lesions
• Drugs/toxins
Differential: Drugs/Toxins
• Acetaminophen
• Alcohol (chronic use depletes glutathione
stores)
• Antidepressants: amitriptyline, nortriptyline
• Oral hypoglycemics: roglitazone, troglitazone
• Antiepileptics: phenytoin, valproate
• Antibiotics: tetracycline, amox/clav, cipro,
doxy, erythromycin, isoniazid, nitrofurantoin
TOXINS
• Anesthetic agents: halothane
• Statins
• Immunosuppressants: cyclophosphamide,
methotrexate
• Salicylates: Reye syndrome
• Gold
• Disulfiram
• Propylthiouracil
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 Drugs
Ecstasy
Cocaine
Herbal Supplements
Ginseng
Pennyroyal oil
Teucrium polium
Chaparral or germander tea
Kava Kava (kawa kawa)
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, HELLP
• Worldwide
▫ HBV +/- HDV
▫ HEV (particularly in pregnant women in Mexico, Central America, India,
SE Asia)
▫ Acetaminophen in Europe, Great Britain
Pathology
• Panlobular necrosis common in medication
related and virally mediated disease
• Centrilobular necrosis extending along the
portal tracts common in acetaminophen
toxicity
• Microvesicular steatosis suggests valproate or
salicylates as primary injury or acute fatty liver
of pregnancy
Laboratory Studies
•
•
•
•
•
•
•
•
•
•
Capillary glucose
•
Ammonia
•
Chemistry
Liver panel w/albumin•
Lipase
Coags (INR >1.5)
Type & screen
•
CBC
•
Lactate
Pregnancy test
•
•
•
Acetaminophen & salicylate level
Toxicology screen
Viral serologies: anti– HAV IgM
– HBV surf ag/ab, core IgM
– HEV
ANA, ASMA, LKMA, Ig levels
Ceruloplasmin (acute phase rxct)
Serum free copper
HIV
Blood cultures
Radiology
• CT Head: cerebral edema, mass lesions
• Liver u/s with dopplers: eval clot, parenchyma
• Liver CT vs MRI: delineate anatomy for possible
transplantation
• EEG: seizures
Complications
•
•
•
•
•
•
Coagulopathy
Encephalopathy
Cerebral edema and herniation
Hypoglycemia
Renal failure
Systemic Inflammatory Response Syndrome (SIRS)
low SVR
• Sepsis
Cerebral Edema
• Vasogenic and cytotoxic in origin
• Ammoniaglutamine which accumulates in
cortical astrocytes
• Increased cerebral blood flow via
–  NO2
–  TNF alpha
–  IL6
–  IL2
–  bacterial endotoxin
Initial management
• Labs as indicated
• Triage to appropriate service: consider ICU
when grade II encephalopathy is present for
freq neuro checks
• N-acetylcysteine
• Intubation if GCS <8, grade III encephalopathy
• Use short-acting , low dose meds only
• Head CT
Encephalopathy
– Grade I
• Confused, altered mood
– Grade II:
• Inappropriate, drowsy
– Grade 3:
• stuporous but arousable, markedly confused
– Grade 4:
• Coma, unresponsive to pain
Mangement: Antidotes
N-acetylcysteine
• Load 140mg/kg, then 15mg/kg/hr
• Pharmacy infusion protocol (call them!)
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)
Management: Coagulopathy
• Correction of coagulopathy not indicated unless
active bleeding is present or procedure
– FFP ( fresh frozen plasma) 15ml/kg or 4 units
– cryoprecipitate
– Factor VIIa for unresponsive bleeding 4mcg/kg
push
– Platelet transfusion only <10K or procedure <50K
Management: Renal Failure
• 1/3 of patients will develop oliguric ARF
• Fluid resusciation
• CVVHD (Continuous veno-venous
hemodialysis) as indicated
• Avoid nephrotoxic medications
• Avoid NSAIDS
Management: CV and Endocrine
• Fluid resuscitation
• Low SVR with normal or increased CO
• Dopamine or norepinephrine prn
•
•
•
•
Impaired gluconeogenesis
Frequent capillary blood glucose q1/2
D5/10 containing solution as necessary
Montior potassium, phosphate and
magnesium
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 hypotension
– Zosyn( Piperacillin/tazobactam) and fluconazole
considered initially. In hospital-acquired IV catheter
infections, consider vancomycin.
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 coma
• Hypothermia is under investigation
• Seizure control with phenytoin
• Call neurology/neurosurgery early
• Refractory increased ICP or decreased CPP is a contraindication for transplantation in most centers
Prognosis: King’s College Criteria
Acetaminophen toxicity
• Arterial lactate >3.5 4 hrs after resuscitation
or
• pH <7.30 or lactate >3.0 12 hours after
resuscit. or
– Arterial pH <7.3
– PT >100 sec
– Creatinine >3.4
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/dL
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)] + 6.43
• Utilized to prioritize transplant recipients
• In 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
METAVIR score
•
Portal (piecemeal necrosis)
Lobular activity
none
none or mild
•
0
1
focal PN, some tracts
1
•
•
•
diffuse PN some tracts OR
PN (grade2)
focal PN all tracts
grade 2
at least 1 focus per lobule
multiple foci per lobule OR
bridging necrosis
•3 diffuse PN all tracts
•
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
•
ACTIVITY GRADE **
A0: no PN or lobular activity
A1: mild PN (grade 1)
A2: moderate
OR lobular
A3: PN grade 2 & lobular gr 2
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
C. Ishak (modified Knodell) score
Necroinflammatory 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 portalcentral linkage
5 marked bridging (P-P and P-C) with occasional nodules (incomplete cirrhosis)
6 cirrhosis
Management: Transplant
• Prior to orthotopic txplt, mortality >80%
• 6% of OLT due to fulminant hepatic failure
• Mortality now around 20-40% center
dependent
• CALL THE TRANSPLANT TEAM TO DISCUSS THE
CASE
REMEMBER:
• Fulminant hepatic failure is incredibly deadly
so triage and treat aggressively
• Get other smart people involved quickly
• Don’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