CHRONIC HEPATITIS AND

MANAGEMENT OF CHRONIC

HEPATITIS-B AND C

DR ANSUMAN DASH

GUIDE – DR. S. K. SETHI

INTRODUCTION

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

• Milder forms are non-progressive or only slowlyprogressive, while more severe forms may beassociated with scarring and architecturalreorganization, which, when advanced, leadultimately to cirrhosis.

CLASSIFICATION

OLD CLASSIFICATION

CHRONIC PERSISTENT HEPATITIS

CHRONIC LOBULAR HEPATITIS

CHRONIC ACTIVE HEPATITIS

It was based on histopathological distinction

NEW CLASSIFICATION

CAUSE

GRADE

STAGE

CLASSIFICATION BY CAUSE :-

TYPE OF HEPATITIS DIAGNOSTIC TEST

Chronic hepatitis B HBsAg, IgG Anti-HBc, HBeAg,HBV DNA

Chronic hepatitis C Anti-HCV, HCV RNA

Chronic hepatitis D Anti-HDV, HDV RNA, HBsAg, IgG Anti-HBc

Autoimmune hepatitis ANA , Anti-LKM1, Hyperglobulinemia

Drug induced hepatitis

Cryptogenic hepatitis All tests negative

CLASSIFICATION BY STAGE

PATHOGENESIS

Direct injury

Immune mediated injury to hepatocyte or biliary epithelium

Promotion of fibrosis

COMMON CLINICAL FEATURES

Hepatitis B

Infection of liver parenchymal cells caused by HBV.

Also known as Serum hepatitis.

Incubation period is long (30 – 180 days).

WHO estimates that 400 million people worldwide are chronicHBV carriers.

India has about 40 million HBV infected patients according toILBS.

Transmission may be horizontal i.e. by exposure to infected bloodor blood products, by needle sharing, sexual transmission or byoccupational exposure.

Vertical or Perinatal transmission.

Slide 4

1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J ClinGastroenterol. 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 VIRUS

HBV is a DNA virus of42 nm virion size.

Double shelled virion.Has 3.2 kb circularDNA.

DNA polymerase isreverse trancriptase.

RISK FACTORS

Horizontal transmission in mainly low endemic areas by exposure to infected blood or other body fluids(sexual route), needle sharing among IV drug abusers, occupational exposure to infected blood or blood products, persons receiving transfusion of infected blood, hemodialysis patients

Vertical transmission mainly in high endemic areas by perinatal transmission from HBsAg +vemothers.

PATHOGENESIS OF HBV

Infection occurs in liver where necrosis probably results from cytotoxic T-cell response,

direct cytopathic effect of HBcAg and high level of HBsAg expression.

PHASES OF HEPATITIS B

INFECTION

WORK UP

Liver function test- ALT & AST usually around 1000 U/L at the onset of jaundice.

CBC

Hepatitis B serology i.e. HBsAg, Anti HBs, HBeAg, Anti Hbe, Anti HBc

Liver Biopsy rarely indicated

USG – to document reduction in liver size ar detect any mass.

Fibroscan (Transient elastography)

Acute HBV Typical serological course

Significance of serological markers

Clinical course of HBV

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 failureHepatocellular carcinoma

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

TREATMENT

Main goal of treatment of Chronic Hepatitis B is to prevent progression to cirrhosis , hepatic failure and HCC.

7 drugs have been approved to date

Injectable Interferon 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 havepredominantly 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 lamivudinemonotherapy 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 ispretreatment ALT level. other being histologic activity, lowHBV 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

Definition of Response to Antiviral

Therapy of Chronic Hepatitis B

Chronic Hepatitis C

Infection of liver parenchyma caused by Hepatitis C virus (ssRNA Flavivirus).

Also known as Transfusion related non-A , non – B hepatitis.

Incubation period is average 6 weeks.

HCV infects more than 185 million individuals worldwide.

Global studies estimate that there are 8.7 million people living with chronic HCV in India.

Shows slight male predominance with highest prevalence in 30 – 49 yr age group.

RISK FACTORS OF HCV INFECTION

Natural history

Clinical Presentation

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

Some have symptomatic liver disease.

Fatigue is the most common symptom.

Dull right upper quadrant pain.

Less common-anorexia, nausea, pruritus, arthralgia, myalgia.

WORK UP

LFT – ALT levels elevated. Unreliable because it fluctuates. Billirubin may be five times normal.

Anti HCV antibody. It takes 6 wks to 12 months to develop HCV Ab. ELISA is the test for HCV Ab. False –ve occur in immune compromised, HIV, renal failure patients. False +ve in autoimmune hepatitis.

HCV RNA detection by qualitative and quantitative PCR. It is used to confirm viremia and to assess response to treatment.

Viral genotyping. It is useful in choosing therapy.

WBC, ESR, PT are usually normal.

TREATMENT OF CHRONIC HEPATITIS C

RESPONSE TO TREATMENT

Autoimmune Hepatitis(AIH)

It is a chronic inflammatory condition of liver characterized by elevated serum globulin (IgG) levels, presence of circulating autoantibodies , interface hepatitis on histology and plasma cell rich infiltrate.

Also known as Plasma cell hepatitis.

Two types – Type 1 AIH most common type. Positive for ANA and Anti-SM antibody with specific HLA haplotypes B8, DR3, DR4

Type 2 is less common and primarily affects children. Anti LKM1 antibody or Anti liver cytosol 1 antibody. HLA DQB1 and DRB1 association.

Female predominance

PATHOGENESIS

Both cell mediated and humoral mechanisms appear to play a role in pathogenesis.

Some studies suggest that CD4 lymphocytes become sensitized to hepatocyte membrane protein.

Molecular mimicry by cross reacting antigens may play a role.

Arthralgia, arthritis, vasculitis and glomerulonephritis occurring in autoimmune hepatitis appear to be mediated by deposition of circulating immune complexes.

CLINICAL FEATURES

Mostly asymptomatic

Fatigue, malaise, anorexia, arthralgia, acne, jaundice are common.

Occasionally arthritis, maculopapular rash, erythema nodosum, sicca syndrome, pleurisy and pericarditis occur.

Some patients present with complications of cirrhosis such as ascites and edema.

Lab findings may include presence of Rheumatoid factor, ANA, Hypergammaglobulinemia, moderate serum bilirubin elevation, near normal ALP and increased ALT levels.

DIAGNOSIS

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

Indications for treatment

Absolute RelativeSerum 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

Goals of Treatment

Induce remission

Prevent disease progression

Minimize relapse of disease

Improve survival

Minimize medication side effects

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

PATHOGENESIS

Clinical features

Asymptomatic in majority of cases

Fatigue

Right upper quardant pain or discomfort

Hepatomegaly (50%)

Obesity

Hypertension

DIAGNOSIS

NAFLD is a diagnosis of exclusion.

Ultrasonography- helps in detecting the fatty infiltration of the liver and helps in determining the size of the liver.

Liver Biopsy - Gold standard for both diagnosis and prognosis. Shows characteristic macrovesicular steatosis with occasional vesicular fat.

Management of NAFLD