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”

5

A

Viral hepatitis NA:NB

E Entericallytransmitted

“Serum” B D CParenterallytransmitted

F- MutantOf B

G

Type of Hepatitis

A B C D E

Source ofvirus

Feces BloodBlood derived

Body fluids

BloodBlood derived

Body fluids

BloodBlood derived

Body fluids

Feces

Route ofTransmission

Feco-oral PercutaneousPermucosal

PercutaneousPermucosal

PercutaneousPermucosal

Feco-oral

ChronicInfection

No Yes Yes Yes No

Prevention Pre PostExposure

Immunization

Pre PostExposure

ImmunizationBlood donor

screening

Blood donor screening

Pre PostExposure

Immunization

EnsureSafe

Drinkingwater

6

7

Hepatitis B Virus

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

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Parenteral - IV drug abusers, health workers are at increased risk.

Sexual - sex workers and homosexuals are particular at risk.

Perinatal (Vertical) –mother (HBeAg+)→infant.

HBV: Modes of Transmission

Properties of HBV

• a member of the hepadnavirus group• Circular partially double-stranded DNA viruses • Replication involves a reverse transcriptase.

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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

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 unknown

Serology

• Antigen Detection- HBsAg,HBcAg,HBeAg• Antibody Detection-Anti HBc, Anti-HBe, Anti-

HBs• DNA Detection- HBV DNA

Diagnosis

Clinical FeaturesIncubation period: Average 60-90 days Range 45-180 daysInsidious 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 symptomsClinical 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%

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.

HBsAg negativeantiHBc negative susceptible

antiHBs negative

HBsAg negativeantiHBc positive immune due to natural infectionantiHBs positiveHBsAg negativeantiHBc negative immune due to vaccineantiHBs positiveHBsAg positiveantiHBc ( total ) positive acutely infectedIgM antiHBc positiveantiHBs negativeHBsAg positiveantiHBc ( IgG) positive chronicallyIgM antiHBc negative infectedantiHBs negativeHBsAg negativeantiHBc ( IgG) positiveantiHBs negative

Interpretation of Hepatitis B Panel

1.resolution of chronic infection2. “window period” infection3. false-positive anti-HBc4. 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-negativeimmune active

• HBsAg present occurs in 20-30% of patients• HBeAg 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 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 long-term

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

DeathDeath

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 cancerNot achieved by the majority of patients

Histological Improvement

Options in treatment

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 Time

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

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AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]

HBV DNA, IU/mL > 20,000 > 20,000 ≥ 2,000ALT, 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

AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]

HBV DNA, IU/mL > 20,000‡ > 2000 ≥ 2000ALT, 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

Selecting an Interferon-Based Initial HBV Treatment

Factors Associated With Choosing Interferon for Initial Therapy

Favorable predictors of responseGenotype A or B > C or D

Low HBV DNA (baseline and on treatment)

High ALT (baseline)

Specific patient demographicsYounger people

Young woman wanting future pregnancyPatient preference

No coinfection with HIV

Concomitant HCV infection

Months

Depression

Fatigue

Flu-like symptoms

Anxiety

1 2 3 40

Incr

ease

in

Inci

denc

e/Se

verit

y

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Patients should be carefully monitored for adverse eventsMost common adverse events: flu-like symptoms (fever, chills, headache,

malaise, and myalgia) as well as psychological impairment

PegIFN Treatment-Associated Adverse Effects

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 DNAconcentration of less than 2000 IU/ml at 24 weeksof therapy.

• Serological response is defined by HBe seroconversionin 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.

.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

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

hypervariableregion

capsid envelopeprotein

protease/ helicase RNA-dependentRNA polymerase

c22

5’

core

E1 E2 NS2

NS3

33c

NS4

c-100

NS5

3’

Hepatitis C Virus

Hepatitis C VirusGenome resembled that of a flavivirus

positive stranded RNA genome of around 10,000 bases1 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 unknownHCV has been classified into a total of six genotypes (type 1

to 6) on the basis of phylogenetic analysisGenotype 1 and 4 has a poorer prognosis and response to

interferon therapyIn Hong Kong, genotype 1 accounts for around 67% of cases

and genotype 6 around 25%.

HCV replicates exclusively in the cytoplasmvia an RNA intermediate

Nucleus

Viral entry & uncoating

Translation & processing(+)

(+)

(-)

(+)

HCV RNAreplicationVirus particle

assembly Replicativeintermediate

Clinical Features of HCV Infectionin 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

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 Features

Hepatitis C

– Nausea– Loss of appetite– Vomiting– Fatigue– Fever– flu-like symptoms– muscle pain– joint pain

– Dark urine– Pale stool– Jaundice– Stomach pain– Side pain– cognitive changes– depression,– headaches, – and mood swings.

• Symptoms

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 Ig ↑↑• The ratio of A/G ↓

Bilirubin • Urobilinogen ↑in early stage of AIH

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 anti-HBs– HBcAg anti-HBc– HBeAg anti-Hbe

• Molecular biological marker – DNAp– HBV DNA– Immune tissue chemistry

examination

Detection of the markers of hepatitis virus:

Hepatitis C• Serological marker

– Anti-HCVIgM– Anti-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 D• HDAg anti-HDV• HDV RNA

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

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Symptoms

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4

Hepatitis C Virus InfectionTypical Serologic Course

Titre

Months YearsTime after Exposure

• 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.

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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.

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HCV RNA (PCR testing)

Virus load Lower detection limit can be 10-615 IU/ml

NOT a predictor of disease severity: a high viralload does not mean the liver disease is moresevere, 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 treatment

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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.

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 -

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TreatmentCHILDREN

• 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

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 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 IFN-ineligible 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 treatment-naive 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 treatment-naive 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 IFN-eligible persons with HCV genotype 3.

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OUTCOMES of HCV hepatitis

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Screening of blood, organ, tissue donors

High-risk behavior modification

Blood and body fluid precautions

Prevention of Hepatitis C

76

HEPATITIS D VIRUS(HDV, DELTA AGENT)

VIRION: spherical, 36-38 nm,HBV capsid, HDV nucleoproteinNUCLEIC ACID: (-) ss RNA, circularSatellite virus : replicates onlyin the presence of HBV

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

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 Features

Consequences of hepatitis B and delta virus infection

80

Percutaneous exposures injecting drug use

Permucosal exposuressex contact

Hepatitis D Virus Modes of

Transmission

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

CirrhosisDefinition: 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 classificationMicronodular 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 cirrhosisSigns:

Jaundice

Fetor hepaticus

Pedal oedema

Generalized wasting

Hands: Leuconychia, clubbing, Jaundice, Flapping tremor, palmar erythema, dupuytren’s contructure

Clinical Feature of cirrhosisParotid enlargement Loss of secondary sexual hair, axillary and pubicGynaecomastia 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 cirrhosisAbdomen :

Dilated abdominal vessels, caput medusa

Ascitis

Splenomegaly

Hepatomegaly

Haemorrhoid

• Ascites is suggested by the following findings on physical examination:

• Abdominal distention• Bulging flanks• Shifting dullness• Elicitation of a "puddle

sign" in patients in the knee-elbow position

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, concentration, intellectual function, coordinationGrade 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 incomprehensibleGrade 4 - Coma, with or without response to painful stimuli

Lab investigationsLiver function: serum albumin and prothrombin are

the best indicator of liver functions. o Albumin is less than 28 g/loProthrombin time increase according to the

severity of the diseaseoSerum bilirubin is elevated

Liver biochemistry: this can be normal depending on the severity of the cirrhosisoALP is elevatedoALT 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 investigationsOther 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 CirrhosisPoor 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

Prognosis of Cirrhosis

• Prognosis can be assessed by using CHILD-PUGH CLASSIFICATION

Parameter

Ascitis None Mild Moderate/ Severe

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. Ascitis2. Spontaneous bacterial peritonitis3. Heamatemesis4. Encephalopathy5. Hepatocellular carcinoma6. Hepato renal syndrome 7. 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 mediatedBacillus cereus toxin Cyanobacteria toxin Organic solvents (eg, carbon tetrachloride) Yellow phosphorus (fireworks)Amanita phalloides mushroom toxinGalerina mushrooms

Illicit DrugsEcstasyCocaine

Herbal SupplementsGinseng 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• Ammoniaglutamine 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: AntidotesN-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 contra-

indication 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

MELDModel 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 ACTIVITY GRADE **

• 0 none none or mild A0: no PN or lobular activity

1 focal PN, some tracts at least 1 focus per lobule A1: mild PN (grade 1)

2 diffuse PN some tracts OR multiple foci per lobule OR A2: moderate• PN (grade2)• focal PN all tracts bridging necrosis OR lobular • grade 2

•3 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•

• 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 portal-

central 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

• Think