CHRONIC VIRAL HEPATITIS

Guide : Dr. Anjali Metgudmath co guide : Dr. Dnyanesh morkar Dr. Santosh hazare Presenter :Dr Yeshavanth G

Scheme of presentation
1.

2.
3. 4. 5. 6. 7. 8. 9. 10. 11.

Introduction Epidemiology Chronic Hepatitis B Epidemiology Definitions Diagnostic criteria mode of transmission Symptoms and signs Extrahepatic manifestations Natural history diagnosis Complications and sequelae Vaccination. Treatment.

1. 2. 3. 4. 5. 6. 7. 8. 9.

Chronic Hepatitis C
Epidemiology Definitions mode of transmission

Symptoms and signs

Extrahepatic manifestations Natural history diagnosis

Complications and sequelae

Treatment.

Introduction

Chronic hepatitis is a clinicopathological syndrome, defined clinically by evidence of liver disease for at least 6 consecutive months and characterized by varying degrees of hepatocellular necrosis and inflammation. Chronic viral hepatitis is caused by hepatitis C hepatitis B and hepatitis D(now almost obsolete)

Etiology of newly diagnosed cases of chronic liver disease

Hepatitis B virus infection

The no of cases has decreased markedly due to universal vaccination, better screening of blood and blood products, increased awareness of stds. identified in almost every body fluid. sexual contact and perinatal transmission The likelihood of perinatal transmission of HBV correlates with the presence of HBeAg and high-level viral replication
The >350400 million HBsAg carriers in the world constitute the main reservoir of hepatitis B in human

High-Risk Populations for Which HBVInfection Screening Is Recommended

Household and sexual contacts of persons with hepatitis B Persons who have used injection drugs Persons with multiple sexual contacts or a history of sexually transmitted disease Men who have sex with men Inmates of correctional facilities Persons with elevated alanine or aspartate aminotransferase levels Persons with HCV or HIV infection Hemodialysis patients Pregnant women Persons who require immunosuppressive or cytotoxic therapy Persons born in countries/regions with a high (>8%) and intermediate (>2%) prevalence of HBV infection

Epidemiological patterns of HEP B infection

Prevalence
Carrier rate Geography

High
8-20 %

Intermediate
3-7%

Low
0.1-2%

Southeast asia Mediterranean Usa and , latin canada america,indian

Predominant age at infection

Mode of transmission

perinatal

early childhood

adult

Maternal infant percutaneous sexual

Few important definitions

Chronic hepatitis B Chronic necroinflammatory disease of the liver caused by persistent infection with hepatitis B virus. Chronic hepatitis B can be subdivided into HBeAg positive and HBeAg negative chronic hepatitis B.

Inactive HBsAg carrier state Persistent HBV infection of the liver without significant, ongoing necroinflammatory disease.

Resolved hepatitis B

Previous HBV infection without further virological, biochemical or histologic evidence of active virus infection or disease.

Acute exacerbation or flare of hepatitis B

Intermittent elevations of aminotransferase activity to more

Reactivation of hepatitis B: Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B. HBeAg clearance :Loss of HBeAg in a person who was previously HBeAg positive. HBeAg seroconversion:Loss of HBeAg and detection of anti-HBe in a person who was previously HBeAg positive and anti-HBe negative, associated with decrease in serum HBV DNA to <105 copies/mL. HBeAg reversion :Reappearance of HBeAg in a person who was previously HBeAg negative, antiHBe positive.

Diagnostic criteria for chronic hepatitis

1. HBsAg+ >6 m 2. Serum HBV DNA >105 IU/mL (may be lower for HBeAg negative patients) 3. Persistent or intermittent elevation in ALT/AST levels 4. Liver biopsy showing chronic hepatitis (necroinflammatory score 4)

Inactive HBsAg carrier state

1. HBsAg+ >6 m 2. HBeAg, anti-HBe+ 3. Serum HBV DNA <105 Iu/ml (usually <1000 IU/mL) 4. Persistently normal ALT/AST levels 5. Liver biopsy confirms absence of significant hepatitis (necroinflammatory score <4)

RESOLVED HEPATITIS B

1. Previous known history of acute or chronic hepatitis B or the presence of anti-HBc antiHBs 2. HBsAg 3. Undetectable serum HBV DNAb 4. Normal ALT levels

Mode of transmission

Parenteral mode of transmission. Blood and blood products. Percutaneous transmission. Sexual transmission. Perinatal transmission. unlikely to occur at HBV DNA levels below 107 copies/mL

Symptoms and signs

30% to 50% of patients with chronic HBV infection have h/o classical acute hepatitis that progressed to chronic infection. Most of them ASYMPTOMATIC. During exacerbations it may mimic acute hepatitis with fatigue, nausea, anorexia and jaundice. Physical examination of limited value. Stigmata of chronic liver disease spider angioma, palmar erythema and mild hepatomegaly, splenomegaly may be seen.

Extrahepatic Manifestations

1.

Associated with both acute and chronic.(acute>chronic) 10 to 20 % of chronic HBV infection. Mediated by circulating immune complexes. Polyarteritis nodosa: immune complexes cause vasculitis causing multisystem involvement. -CVS,GI, CNS are involved and sometimes can be fatal. -IFN ,steroids,nucleoside analogs are used in treatment.

2)GLOMERULONEPHRITIS: -more in children. -membranous most common. -children usually undergo spontaneous remission. -30% adults progress to renal failure. -steroids are ineffective. -IFN can be tried as rx.

3) essential mixed cryoglobulinemia: GN, arthritis, purpura. 4) papular acrodermatitis: more in children. symmetrical, erythematous, maculopapular, nonitchy eruptions over the face, buttocks, limbs with lymphadenopathy. 5)aplastic anemia.

NATURAL HISTORY

overall rate of progression from acute to chronic HBV infection has been estimated to be 5% to 10%. Risk inversely proportional to age at infection. Hepatitis B Virus Infection is a Life-Long Infection.

Outcome of Hepatitis B Virus Infection by Age at Infection 100

Chronic Infection (%)

100 80

80

Symptomatic Infection (%)

60

Chronic Infection
Chronic Infection (%)

60

40

40

20

20

Symptomatic Infection
0 Birth 1-6 months 7-12 months 1-4 years 0 Older Children and Adults

Age at Infection

Natural history of chronic HBV infection in adults

Natural history of chronic HBV infection in perinatal infection

Diagnosis serologic markers

Hepatitis B surface antigen Hepatitis B e antigen Anti-HBe Anti-HBc (IgM) Anti-HBc (IgG) Anti-HBs Anti-HBc (IgG) + anti-HBs Anti-HBc (IgG) + HBsAg HBV infection: acute or chronic High levels of HBV replication and infectivity Low levels of HBV replication and infectivity Recent HBV infection Recovered or chronic HBV infection Immunity to HBV infection Past HBV infection Chronic HBV infection

Diagnosis of Hepatitis B Virus (HBV) Infection

Chr HBs onic Ag HBV Infec + tion + HBeA g + IgM IgG anti- anti HBc HBc + Anti HBs Anti Hbe HBV Dna +++ Interpretatio n HBeAG+ chronic hepatitis Inactive carrier state HBeAgchronic hepatitis Exacerbation s of chronic hepatitis

++

++

Possible Outcomes of HBV Infection

Acute hepatitis B infection
3-5% of adult-acquired infections Chronic HBV infection 95% of infantacquired infections

Chronic hepatitis 12-25% in 5 years

6-15% in 5 years
Hepatocellular carcinoma
Death

Cirrhosis

20-23% in 5 years Liver failure

Liver transplant

Death

Sequelae of Chronic Hepatitis B Virus Infection

Range from inactive carrier state to chronic hepatitis, cirrhosis, hepatic decompensation, HCC and death. Depends on severity of liver damage prior to sustained sero conversion and durability of inactive carrier phase. rate of progression from chronic hepatitis to cirrhosis: 2-6% in HBeAg-positive and 8-9% in HBeAg-negative patients.

Annual rate of progression from compensated cirrhosis to hepatic decompensation has been estimated to be 4% to 6%. lifetime risk of a liver-related death was estimated to be 40% to 50% for men and 15% for women. Annual rate of HCC development has been estimated to be 0.5% to 1.0% for noncirrhotic carriers and 2.5% to 3% for patients with cirrhosis

Factors associated with worse outcome

Host(older age, men), virus (persistent high levels of HBV replication, HBV genotype [C > B], coinfection with HCV, HDV, and HIV), environment (alcohol and more recently obesity)

Hepatitis B Vaccines and Dosage Recommendations

infants born to HBsAg-negative mothers and unvaccinated children/adolescents up to 19 years of age, 3 doses (0, 1 and 6 months) of vaccine at half strength ( 10 micrograms) to be given. For adults >20 years of age full dose (20 micrograms) is given. newborns of HBsAg carrier mothers, HBIG 0.5 mL and the first dose of vaccine should be administered at birth, using different sites. For patients on hemodialysis or immunocompromised patients, higher doses of

Indications for Hepatitis B Vaccine

1. All newborns 2. All children and adolescents not vaccinated at birth 3. High-risk adults: a. Health care workers b. Men who have sex with men c. Persons with multiple sexual partners d. Injection drug users e. Patients on hemodialysis f. Institutionalized patients g. Health care workers and public safety workers h. Spouse, sexual partners and household members of HBV carriers

Vaccination contd

1.

2.

A protective response defined as an anti-HBs titer more than 10 IU/L. 2.5% to 10% of vaccine recipients fail to respond with adequate anti-HBs titers. BOOSTER DOSE: NOT recommended routinely considered in those who are immunocompromised or at a high risk of exposure. recommended booster vaccination approximately 10 to 15 years after primary vaccination First vaccine to prevent cancer in humans.(HCC) Extremely safe vaccine. Newer combination vaccines are available(easy 5)

CHRONIC VIRAL HEPATITIS

Guide : Dr. Anjali Metgudmath co guide : Dr. Dnyanesh morkar Dr. Santosh hazare Presenter :Dr Yeshavanth G

Post exposure prophylaxis

unvaccinated persons : HBIG + hepatitis B vaccine Perinatal (HBsAg-positive mothers) : HBIG, 0.5 mL,(immediately after birth) + complete course of 3 injections of recomb hep B vaccine started within the first 12 hours of life. Direct percutaneous inoculation or transmucosal exposure to HBsAg-positive blood or body fluids HBIG, 0.06 mL/kg, administered as soon after exposure as possible, is followed by a complete course of hepatitis B vaccine to begin within the first week.

Treatment of Chronic Hepatitis B

APPROVED TREATMENTS IN THE UNITED STATES Standard Interferon- 2b Pegylated Interferon- 2a Lamivudine Adefovir dipivoxil Entecavir TREATMENTS APPROVED FOR HUMAN IMMUNODEFICIENCY VIRUS WITH EFFICACY AGAINST HEPATITIS B VIRUS Emtricitabine Tenofovir Emtricitabine + Tenofovir

Definition of Response to Antiviral Therapy of Chronic Hepatitis B

Biochemica Decrease in serum ALT to within the normal range l

Virological

Decrease in serum HBV DNA to <105 IU/mL and loss of HBeAg in patients who were initially HBeAg positive; undetectable serum HBV DNA (<102 IU/mL) in patients who were initially HBeAg negative
Decrease in histologic activity index by at least two points compared to pretreatment liver biopsy Fulfill criteria of biochemical and virological response and loss of HBsAg

Histologic

Complete

Comparison of Percentages of Patients with Antiviral Responses to Approved Treatments of Hepatitis B

Interferons

antiviral, antiproliferative and immunomodulatory effects. IFN- and - bind to the same receptor and have predominantly antiviral effects. IFN- binds to a separate receptor and has more marked immunoregulatory action. Pegylation reduces rate of absorption,renal clearance, decreases immunogenecity and increases half life.

The recommended dose is 180 g weekly for 48 weeks. pegIFN-2a monotherapy was superior to lamivudine monotherapy in inducing HBeAg seroconversion. a/e include initial flu like illness, fever, chills, headache, malaise, myalgia, emotional liability. The strongest predictor of response in HBeAg+ patients is pretreatment ALT level. other being histologic activity, low HBV dna level,HBV genotypes.

Lamivudine

A nucleoside analogue causes chain termination. effective in suppressing HBV replication and in ameliorating liver disease. One-year treatment with lamivudine results in similar rate of HBeAg seroconversion as 16 week of standard IFN-, but is inferior to a 1year course of pegIFN-. recommended dose for adults with normal renal function (creatinine clearance >50 mL/min) and no HIV infection is 100 mg daily PO

Patients with HIV coinfection should be treated with 150 mg b.i.d. doses. minimum of 6 months after confirmed HBeAg seroconversion. longer duration of treatment is recommended. criteria for discontinuation of treatment and the optimal duration of therapy have not been established.

Famciclovir : 1)oral prodrug of penciclovir, an acyclic deoxyguanosine analog. 2) low efficacy, need for administration thrice daily, and potential for crossresistance with lamivudine. Adefovir Dipivoxil 1)inhibit reverse transcriptase 2) effective in suppressing wild type as well as lamivudine-resistant HBV 3) 10 mg daily PO

Entecavir: orally administered cyclopentyl guanosine analog. Emtricitabine Tenofovir Telbivudine (sebivo)

Recommended Strategies for Patients with Chronic Hepatitis B

Chronic Hepatitis C infection

most common cause of chronic liver disease accounting for 40 to 60% of cases. Progression to cirrhosis mainly depends on duration of the disease. MC risk factor for new infection, accounting (60%), is intravenous drug use. 50% to 80% of users became anti-HCV positive within 12 months

Etiology of chronic hepatitis c

Health care workers

needle-stick injuries probably account for a large proportion of cases. Skin exposure to blood is NOT a risk factor. anti-HCV seroconversion after accidental needle-stick/sharp exposures averaged only1.8%(greater than HIV or HBV).

Transfusion associated

risk of acquiring post-transfusion hepatitis has declined dramatically(0.01% to 0.001% per unit transfused sera). Hemodialysis: approximately 8% of cases. The improved safety of the blood supply, availability of recombinant erythropoietin, phasing out of pretransplant immune conditioning transfusion protocols have significantly reduced the risk of hepatitis C in these patients. Transplantation and sexual transmission although reported the data supporting is less. Perinatal transmission.

Natural History

Approximately 80% of acutely infected patients develop chronic infection (viremia) and most of these (80% to 90%) have chronic hepatitis with elevated ALT levels. Alcohol and other factors accelerate the progress of the disease. asymptomatic elevations of serum aminotransferase levels(mild) . Fatigue, dull right upper quadrant pain, anorexia, nausea, myalgia are the symptoms.

1. 2.

3. 4.

Although most of them developed chronic liver disease, ALL CAUSE MORTALITY remained the same in general populaton. HCV-related HCC rarely occurs in the absence of cirrhosis.(1.4 to 3.3%) Mean duration 30 years. Risk increase wit longer duration, cytopenia, male gender, alcohol use, HBV coinfection, AFP level is elevated Diagnosed by imaging.

1.
2.

Extrahepatic manifestations Mixed cryoglobulinemia Chronic glomerulonephritis these respond to interferons.

Survival in patients with cirrhosis due to chronic hepatitis C. Effect of complications and decompensation

Risk of developing decompensated liver disease among patients with stable cirrhosis due to chronic hepatitis

Prevention and Treatment

Public health guidelines have been issued for HCVINFECTED PERSONS Consider all anti-HCV or HCV RNApositive persons to be potentially infectious Do not donate blood, organs, tissues, or semen

Avoid sharing of household items such as toothbrushes and razors

Changes in sexual practices are not required within a monogamous relationship (however, a low potential for sexual HCV transmission exists; anti-HCVpositive persons and their partners should be informed of the potential risk of sexual transmission and an informed decision regarding the need for precautions should be made) Vaccinate against hepatitis A and B

The role IVIg is being studied.(not yet proved) Post exposure care:persons with percutaneous exposure to HCV should be closely monitored for infection(serial testing of serum ALT and anti-HCV levels at baseline and 4 to 6 months postexposure) No vaccine as yet available now.

Treatment

1.

2. 3.

Major goal is to prevent the development of decompensated liver disease and death. In chronic infection, goal eradicate or prolonged suppression of viral replication, reduction of hepatic inflammation, slowing the rate of progressive liver injury

Peg IFN + Ribavirin >>>>> IFN/ Ribavirin monorx. Viral genotype has an important effect on response to treatment. Std rx consist of Peg IFN a-2b (1.5g/KBW) or pegylated IFN -2a s/c once per week and 13 to 15 mg/kg of oral ribavirin per day.

Interferon and Ribavirin Dosing According to Viral Genotype

Dosing Guidelines for Combination Therapy with Pegylated Interferon and Ribavirin

Definitions of Treatment Responses

In typical cases of acute hepatitis C, recovery is rare, progression to chronic hepatitis is rule, and metaanalyses of small clinical trials suggest that antiviral therapy with interferon alfa monotherapy (3 million units SC three times a week) is beneficial, reducing rate of chronicity considerably by inducing sustained responses in 3070% of patients Although treatment of acute hepatitis C is recommended, optimum regimen, duration of therapy, and time to initiate therapy remain to be determined. Many authorities now opt for a 24-week course (beginning within 23 months after onset) of the best regimen identified for the treatment of chronic hepatitis C, long-acting pegylated interferon plus the nucleoside analogue ribavirin, although value of adding ribavirin has not been demonstrated

Hepatitis D

HDV can either infect a person simultaneously with HBV (co-infection) or superinfect a person already infected with HBV (super-infection) Obsolete now. Only drug used in treating was IFN-a

Hepatitis G

asymptomatic course Role in liver disease not yet proven co infection with HGV and HIV has been shown to improve mortality and morbidity for the HIV-infected individuals and slow the progression to AIDS. Herpes viruses also cause hepatitis.

Take home messages

Chronic viral hepatitis is definitely TREATABLE and also CURABLE in many cases. Early identification and initiation of rx. Many patients ARE being treated and good responses have been obtained. HBeAg negativity does not always mean good prognosis(it can be an indicator of resistant mutants) Universal vaccination for hep b. Post exposure prophylaxis. Avoidance of additional hepatotoxic

Treatment is not very cumbersome and quite patient friendly. Active research is going on in this field and lot of new treatment and guidelines are coming up.

REFERENCES

Schiff's Diseases of the Liver, 10th Edition CHRONIC VIRAL HEPATITIS DIAGNOSIS AND THERAPEUTICS by RAYMOND S. KOFF, MD and GEORGE Y. WU, MD, PhD. Diseases of the Liver and Biliary System by sheila sherlock Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Harrisons principles of internal medicine 18th edition Internet International conference on viral hepatitis.

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