Presenter Dr Vamshi A

Guide : Dr V A Kothiwale

Co Guide : Dr Rajeev Malipatil

CHRONIC HEPATITIS

Content

INTRODUCTION AND DEFINITION

CLASSIFICATION

CAUSES

Introduction

• Chronic hepatitis represents a series of liver disorders of varying causes and severity in which hepatic inflammation and necrosis continue for at least 6 months.

• Milder forms are nonprogressive or only slowly progressive, while more severe forms may be associated with scarring and architectural reorganization, which, when advanced, lead ultimately to cirrhosis.

Classification

Cause Grade Stage

By Cause

By Grade

Histologic Activity Index(HAI)

HAI Score

By Stage

Different types of chronic hepatitis Hepatitis B Hepatitis C NAFLD ALCOHOLIC HEPATITIS AUTOIMMUNE HEPATITIS RARE CAUSES- GENETIC & DRUGS

Hepatitis B

Slide 4

1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158. 3. WHO/WPRO data.

HBsAg Prevalence (%)1

High Intermediate < Low

Country HBsAg+ (%)

China 5.3-122

South Korea 2.6-5.12

India 2.4-4.72

Taiwan 10-13.82

Vietnam 5.7-102

Japan 4.4-133

Africa 5-192

Russia 1.4-82

US/Europe 0.3-122

Geographic Distribution of Chronic HBV Infection

Hepatitis B significance of serological markers

Acute HBV Typical serological course

IgM anti-HBc

Total anti-HBc

HBsAg

Acute(6 months)

HBeAg

Chronic(Years)

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

Weeks after Exposure

Titre

Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course

Clinical course of HBVAcute 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

6-15% in 5 years 20-23% in 5 years

Phases of chronic hepatitis B

Diagnosis of Hepatitis B Virus (HBV) Infection

Chronic HBV

HBsAg

HBeAg

IgM anti-HBc

IgG anti HBc

Anti HBs

Anti Hbe

HBV DNA

Interpretation

Infection

+ + - + - - +++ HBeAG+ chronic hepatitis

+ - - + - + + Inactive carrier state

+ - - + - + ++ HBeAg- chronic hepatitis

+ + + + - + ++ Exacerbations of chronic hepatitis

Diagnostic criteria for chronic HBV1. HBsAg+ >6 m

2. Serum HBV DNA >10 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)

5

Slide 12

When to treat HBV?

HBeAg Positive

Treat

Monitor ALT Q3mos for 1y

HBeAg Negative

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

Normal ALT

Consider Liver Biopsy If >40yrs

Significant fibrosis or inflammation

Elevated ALT

ALT Level

Treatment

Main goal of treatment of chronic Hep B is to prevent cirrohosis , hepatic failure and HCC.

Treatment Options

7 drugs have been approved to date Injectable Interferon (INF) α, Pegylated Interferon(PEG), Lamivudine, Adefovir, Entecavir, Telbivudine, Tenofovir.

INTERFERONS

Antiviral, antiproliferative and immunomodulatory effects.

IFN-α and -β bind to the same receptor and have predominantly antiviral effects.

IFN-γ binds to a separate receptor and has more marked immunoregulatory action but less potent antiviral effects.

Pegylation reduces rate of absorption,renal clearance, decreases immunogenecity and increases half life.

The recommended dose is 180 μg weekly for 48 weeks.

pegIFN-α2a 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.

LAMIVUDINE

Nucleoside analogue. Effective in suppressing HBV replication. Recommended dose for adults with normal renal

function (creatinine clearance >50 mL/min) and no HIV infection is 100 mg daily PO

Adefovir Dipivoxil

• Inhibit reverse transcriptase• Effective in lamivudine-resistant HBV• 10 mg daily PO

Entecavir: orally administered cyclopentyl guanosine analog.

Emtricitabine

Tenofovir

Telbivudine (sebivo)

Definition of Response to Antiviral Therapy of Chronic Hepatitis B

Chronic Hepatitis C

Overview: Prevalence: 170 million worldwide New cases/yr: ~3-4 million worldwide Progression to cirrhosis occurs in about 20−25%

followed for 20yrs Leading cause of chronic liver disease,

cirrhosis, HCC.

Clinical Presentation

Most patients with chronic hepatitis have asymptomatic elevations of serum aminotransferase levels and do not have physical signs of liver disease.

6% have symptomatic liver disease. Fatigue is the most common symptom. Dull right upper quadrant pain. Less common-

anorexia,nausea,pruritis,arthralgia,myalgia

Risk factors

Natural history

Treatment

Viral eradication

Prevention of disease progression

Sustained loss of HCV RNA in serum (3-6 mos post-Tx)

Normalization of liver enzymes

Improved liver histology Improved quality of life

Goals Endpoints

Treatment options

Non Alcoholic Fatty Liver Disease(NAFLD)

NAFLD was first described in the 1950s when fatty liver was characterized in a group of obese patients.

In 1980, Ludwig and colleagues at the Mayo Clinic described 20 obese, diabetic, nonalcoholic patients who had similar findings on liver biopsy to patients with alcoholic liver disease, and the term nonalcoholic steatohepatitis was introduced

Signs and symptoms

Asymptomatic in majority of cases

Fatigue

Right upper quardant pain or discomfort

Hepatomegaly (50%)

Obesity

Hypertension

Diagnosis NAFLD is a diagnosis of exclusion

-Alcoholic Hepatitis

-Drug induced Hepatitis (tamoxifen, amiodarone)

-Viral Hepatitis

-Autoimmune Hepatitis

-Metabolic (Wilson and Hemochromatosis)

The most challenging DDX is alcoholic hepatitis

The histologic picture of both conditions is similar

Consumption of alcohol less than 10 g/d in women and 20 g/d in men

Imaging

Ultrasonography- helps in detecting the fatty infiltration of the liver

and helps in determining the size of the liver.

Liver biospy

Gold standard for both diagnosis and prognosis Shows characteristic macrovascular steostosis with

occasional vesicular fat.

Algorithm for Management of NASH

Alcoholic hepatitis

The threshold for developing alcoholic liver disease in men is an intake of >60–80 g/d of alcohol for 10 years, while women are at increased risk for developing similar degrees of liver injury by consuming 20–40 g/d.

Ingestion of 160 g/d is associated with a 25-fold increased risk of developing alcoholic cirrhosis.

Only 10 – 15 % of alcoholics develop cirrohosis.

How is Alcoholic hepatitis diagnosed?

History of recent excessive alcohol ingestion Serum bilirubin more than 80mmol/l ALT <300 IU (or AST<500 IU) Exclusion of autoimmune, chronic viral or

malignant liver disease

Characteristic features of alcoholic hepatitis (but not necessary for diagnosis)

Pyrexia, Hepatomegaly, A hepatic bruit, Ascites, Encephalopathy, AST: ALT ratio greater than 1.5, Peripheral leucocytosis.

Prognosis

Discriminant score:

4.6 x(PTtest – Ptcontrol)+S.bilirubin(mg/dl)

American College of Gastroenterology defines severity as a modified Discriminant Function (mDF)> 32

Autoimmune Hepatitis(AIH)

AIH represents a chronic, mainly periportal hepatitis with lymphocytic infiltrates, plasma cells, and piecemeal necrosis.

Etiology is unclear. Female predominance, hypergammaglobulinemia,

circulating autoantibodies, and a good response to immunosuppressive treatment.

Exclusion of other chronic diseases Viral hepatitis (HBV and HCV) Alcoholic liver disease and NAFLD Drug-induced hepatotoxicity Wilson disease Hereditary hemochromatosis Alpha-1-antitrypsin deficiency Primary biliary cirrhosis Primary sclerosing cholangitis

Severe disease (untreated) 40% die within 6 months of diagnosis 40% of survivors develop cirrhosis 54% of cirrhotics develop varices within 2 years of

diagnosis of cirrhosis 20% of patients with varices will bleed

Clinical features Type 1 Type 2 Type 3

Diagnostic autoantibodies

ASMA

ANA

Antiactin

Anti LKM

PD 450,IID6

Synthetic core motif peptides 254-271

SLP

Cytokeratins 8 & 18

Age 10 y-elderly Pediatric (2-14 y)Rare in adults

Adults (30-50 y)

Women (%) 78 89 90

Concurrent immune disease (%)

41 34 58

Gamma globulin elevation

+++ + ++

Low IgA No occasional No

HLA association

Steroid response

Progression of response

B8, DR3, DR4

+++

48

B14, Dr3, C4AQO

++

82

Uncertain

+++

75

Goals of Treatment

Induce remission

Prevent disease progression

Minimize relapse of disease

Improve survival

Minimize medication side effects

Indications for treatment

Absolute Relative

Serum AST 10-fold or more greater than the upper limit of normal

Symptoms (eg, fatigue, arthralgia, jaundice)

Serum AST 5-fold or more greater than the upper limit of normal and gamma-globulin level 2-fold or more greater than normal

Serum AST and/or gamma-globulin less than absolute criteria

Bridging necrosis or multiacinar necrosis on

histologic examination

Interface hepatitis

Treatment Options

THANK YOU

Slide 7

Natural history of HBV