Chronic hepatitis

Learning objective
At the end of the class the student should be able to:
Define hepatitis and list the causes of chronic hepatitis Discuss the pathology and the clinical features Relevant investigations to diagnose the cause Management principles of chronic hepatitis

Content
Definition of chronic hepatitis Clinical presentation of chronic hepatitis Classification and causes of chronic hepatitis Differentiate the causes based on pathogenesis, patient factors and investigation results Treatments available for chronic hepatitis depending on the cause

Hepatitis
Acute: Short term and/or severe. Chronic: Lingering or lasting - may or may not be severe Fulminant: Developing quickly and lasting a short time, high mortality rate. Cirrhosis: Hardening: may be the result of infection or toxins (e.g. alcohol)

Definition
Hepatitis = inflammation of liver parenchyma with varying degrees of structural damage

Chronic hepatitis = lasting 6 months or longer

Mild forms Severe forms -cirrhosis

Causes
Autoimmune

Drugs

Chronic hepatitis

Hepatitis B +/-D

Wilsons

Hepatitis C

 Histological grade = necro-inflammatory activity (minimal, mild, moderate, severe) Histological stage = extent of fibrosis (none, mild, moderate, severe, cirrhosis) Knodel Ishak scoring: based on periportal necrosis, intralobar necrosis, portal inflammation and fibrosis.
Important in predicting development of cirrhosis

0 = no 1-4 = minimal 5-8 = mild 9-12 = moderate 13-18 = marked

Clinical presentation
Fatigue, generally unwell Jaundice, large liver Positive blood test (Hep B/C): before blood donation, before dialysis or surgery, routine pre-employment screening Failure to recover (clinically or biochemically) from acute hepatitis Abnormal LFTs on routine check up Previous blood transfusion Previous IV drug use/vertical transmission

Chronic Hepatitis B
The likelihood of chronicity after acute hepatitis B varies as a function of age. Infection at birth is associated with clinically silent acute infection but a 90% chance of chronic infection. Infection in young adulthood in immunocompetent persons is typically associated with clinically apparent acute hepatitis but a risk of chronicity of only approximately 1%.

ACUTE

CHRONIC

Natural History of Chronic HBV Infection

90-95% Resolution Stabilisation Compensated Cirrhosis

Acute Infection

Chronic Hepatitis

15-25%
Cirrhosis

Liver Cancer

Death

5-10% Chronic Carrier

Progression

Decompensated Cirrhosis (Death)

Adapted from Feitelson, Lab Invest 1994

3050 Years

Clinical course of HBV in adults

What do we expect from chronic hepatitis B?

Cirrhosis
Compensated Decompensated

Complication of cirrhosis
Ascites Variceal bleeding Hepatic encephalopathy

Hepatocellular carcinoma

HBV-DNA by PCR also indicates active replication of the virus HBV replication = Disease

(Acute or Chronic replicative phase)

Anti-HBc IgM: Acute or present infection Anti-HBc IgG: Chronic or past infection

Investigations
1. Deranged liver function tests 2. Serology: HBsAg + Anti-HBc IgMAcute Hepatitis B HBsAg + IgG HBcAg HBsAg ve (cured) HBeAg HBV DNA HBeAg+ Wild type HBeAgPrecore Mutants HBsAg +ve (carrier)

Precore Mutants
patients with HBeAg-negative chronic hepatitis B (precore mutants) can have progressive liver injury (complicated by cirrhosis and HCC) and experience episodic reactivation of liver disease reflected in fluctuating levels of aminotransferase activity ("flares").

Hepatitis B D
Treatment
All patients with chronic active hepatitis B should receive antiviral agents Interferon- (PEGylation) Lamivudine Ribavirin 100 mg orally daily Adefovir dipivoxil 10 mg orally

Hepatitis B +/-D
Treatment
given to avoid progression to cirrhosis Interferon- + Lamivudine best combination

NNRTI

PI

NRTI
HAART Fusion inhibitors

Integrase inhibitors

Treatment
Seroconversion from HBeAg to anti-HBe occurs in approximately 20%, and, in early trials, approximately 8% lost HBsAg. Relapse after successful therapy is rare (1 or 2%).

PEG IFNb
Route of administration

Lamivudine

Adefovir

Entecavir

Subcutaneous Oral injection

4852 weeks 52 weeks

Oral
48 weeks

Oral
48 weeks

Duration of therapy

Tolerability

Poorly tolerated

Well tolerated

Well tolerated Well tolerated; creatinine monitoring recommended 23% 22%

HBeAg loss 1 year

2930%

2033%

Side effects
Interferon: flu like symptoms, bone marrow suppression, rash, alopecia, numbness, autoimmune reactions.
Lamivudine alone: Mutant side effects Adefovir: rare nephrotoxic

Clinical
HbeAg reactive CH CH

HBV DNA ALT copies/mL Normal or <105

(<2 x ULN) Normal or (<2 x ULN) Elevated (>2 x ULN)

Recommen dation
Not, monitor
liver biopsy and treating if abnormal)

105

105

Treat Treat with oral agent

Cirrhosis +/_ Com/Decom

Nor/

Clinical
HbeAg negative

HBV DNA ALT copies/mL <10-4 -105 Normal or

(<2 x ULN)

Recommen dation
Not, inactive carrier
liver biopsy and treating if abnormal)

CH CH

10-4 -105 10-4 -105

Normal or (<2 x ULN) Elevated (>2 x ULN)

Treat Treat with oral agent

Cirrhosis +/_ Com/Decom

Nor/

Chronic Hepatitis C Factors Promoting Progression or Severity

Increased alcohol intake Age > 40 years at time of infection

HIV co-infection
?Other
Male gender Other co-infections (e.g., HBV)

Serologic Pattern of Acute HCV Infection with Recovery

anti-HCV
Symptoms +/-

HCV RNA

Titer

ALT

Normal 0 1 2 3 4 Months 5 6 1 2 3 Years 4

Time after Exposure

Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection

anti-HCV
Symptoms +/HCV RNA

Titer

ALT

Normal 0 1 2 3 4 Months 5 6 1 2 3 Years 4

Time after Exposure

Hepatitis C
Clinical features
All ages affected and both sexes affected equally Commonly asymptomatic Risk factors for hep C infection present Severity very variable

Diagnostic tests
Anti HCV, HCV RNA Biopsy: Fat, lobular component, lymphoid aggregates

Recombinant immunoblot assay (RIBA) test to help confirm a hepatitis C infection.

Hepatitis C
Treatment
Pegylated Interferon- with ribavirin

Prognosis
Usually very slow progression cirrhosis in 20-30% within 3 decades Variable prognosis depending on age, race and development of cirrhosis

Standard Indications for Therapy

Detectable HCV RNA (with or without elevated ALT) Portal/bridging fibrosis or moderate to severe hepatitis on liver biopsy

Antiviral Therapy Not Recommended Decompensated cirrhosis Pregnancy (teratogenicity of ribavirin)

Therapeutic Regimens
First-line treatment: PEG IFN subcutaneously once a week plus daily ribavirin orally HCV genotypes 1 and 4 48 weeks of therapy
(PEG IFN- 2a 180 g weekly plus ribavirin 1,000 mg/d)

HCV genotypes 2 and 324 weeks of therapy

(PEG IFN- 2a 180 g weekly plus ribavirin 800 mg/d)

Features Associated with Reduced Responsiveness

Genotype 1High-level HCV RNA (>2 million copies/mL or >800,000 IU/mL) Advanced fibrosis (bridging fibrosis, cirrhosis) Long-duration disease Age > 40 Immunosuppession Obesity

AUTOIMMUNE HEPATITIS
Chronic hepatitis of unknown etiology Can progress to cirrhosis Characteristics include:
presence of autoimmune antibody evidence of hepatitis elevation of serum globulins

Autoimmune
Clinical features
More females affected Usually aged 14-25 or post menopausal 25% present with acute hepatitis Associated with other autoimmune diseases

Cause unknown Classified as type 1 (lupoid) , type 2 and type 3

TYPE 1
ANA or Anti-Smooth Muscle antibody positive Titer usually > 1:100 10% will have an antibody to Soluble Liver antigens (SLA) Other Antibodies: anti-DNA, ANCA, Antimitochondrial, Anti-Actin (AAA), cytoskeletal antibody, nuclear envelope proteins lamin A and C, plasma membrane sulfatides

TYPE 1
Bimodal Age distribution (ages 10-20 and 45-70) Female: male (3.6:1) Associated with extrahepatic manifestations:
Autoimmune thyroiditis, graves disease, chronic UC with RA, pernicious anemia, systemic sclerosis, ITP, SLE

40% present with acute onset of symptoms similar to toxic hepatitis or acute viral hepatitis

Clinical features
Type I autoimmune hepatitis is the classic syndrome This is the group with positive lupus erythematosus (LE) preparations (initially labeled "lupoid" hepatitis) in whom other autoimmune features are common.

Fatigue, malaise, anorexia, amenorrhea, acne, arthralgias, and jaundice are common. Occasionally arthritis, maculopapular eruptions (including cutaneous vasculitis), erythema nodosum, colitis, pleurisy, pericarditis, anemia, azotemia, and sicca syndrome (keratoconjunctivitis, xerostomia) occur.

Type II autoimmune hepatitis

Often seen in children More common in Mediterranean populations In type II autoimmune hepatitis, the antibody is anti-LKM1, directed against cytochrome P450 2D6 [anti-Liver/Kidney Microsome Antibodies (LKM1) or anti-Liver Cytosol antibody (ALC-1)] Anti LKM1 often false-positive in hepatitis C

 Another type of autoimmune hepatitis has been recognized, type III autoimmune hepatitis. These patients lack ANA and anti-LKM1 but have circulating antibodies to soluble liver antigen/liver pancreas antigen (Anti-SLA)

CLINICAL PRESENTATION
Hepatomegaly Jaundice Stigmata of chronic liver disease Splenomegaly Elevated AST and ALT Elevated PT Non-specific symptoms: malaise, fatigue, lethargy, nausea, abdominal pain, anorexia

DIAGNOSIS
Elevated AST and ALT Elevated IgG Rule out other causes:
Wilsons disease Alpha 1 antitrypsin deficiency Viral hepatitis (A, B, C) Drug induced liver disease (alcohol, minocycline, nitrofurantoin, INH, PTU, methyldopa, etc) PBC, autoimmune cholangitis

Presence of autoimmune antibodies Liver biopsy

Autoimmune
Treatment
Corticosteroids +/-azathioprine Only treat after biopsy Huge reduction in symptoms + prolongs life

Prognosis
Variable course with relapses Cirrhosis almost inevitable 63% 10 year survival rate

PREDNISONE ONLY
Prednisone 60mg PO daily with a taper down to 30mg at the 4th week into treatment and then maintenance of 20mg daily Reasons for Prednisone only:
Cytopenia Malignancy pregnancy

COMBINATION THERAPY
Prednisone + Azathioprine Prednisone: start at 30mg daily and taper down to 15mg at week 4, then maintain on 10mg daily Azathioprine 50mg daily

Other causes of chronic hepatitis

Drugs Commonly females aged >40 Associated with arthritis, glomerulonephritis, vasculitis Present with jaundice + hepatomegaly Isoniazid, methyldopa, nitrofurantoin, dantrolene, propylthiouracil Diagnosis from history + raised serum liver enzymes Improvement after stopping drug

Kayser-Fleischer Ring

Wilsons disease
Rare inborn error of copper metabolism Presents in childhood with liver + basal ganglia involvement Biopsy shows CAH or cirrhosis Treat with long term penicillamine

Scheme of diagnosis and management

History (Alcohol, IVDU, Sexual promiscuity, family history autoimmune disease, Wilsons disease) + physical examination (Tattoo, needle marks, KF ring) CHRONIC HEPATITIS Double check medications HBsAg/anti-HCV tests

Positive

Negative Autoantibodies Exclude Wilsons + other rare causes

Consider antiviral therapy

Positive Corticosteroids

Type of Hepatitis

Diagnostic Test(s)

Autoantibodies

Therapy

Chronic hepatitis B

HBsAg, IgG antiHBc, HBeAg, HBV DNA Anti-HCV, HCV RNA

Uncommon

IFN-, PEG IFN-,

lamivudine, adefovir, entecavir Anti-LKM1 ribavirin

Chronic hepatitis C
PEG , IFNPEG IFNIFN-

PEG IFN- plus

Chronic hepatitis D

Anti-HDV, HDV RNA, Anti-LKM3 HBsAg, IgG antiHBc ANA (homogeneous), anti-LKM1(), Hyperglobulinemia All negative ANA, anti-LKM1, anti-SLA

IFN-, PEG IFN-

Autoimmune hepatitis

Prednisone, azathioprine

Drug-associated Cryptogenic

Uncommon None

Withdraw drug Prednisone (?), azathioprine (?)

Conclusion
Chronic hepatitis commonly presents with nonspecific symptoms or abnormal blood tests Common causes are viral hepatitis B + C and autoimmune disease A logical investigative pathway should be followed to diagnose the cause Treatment and prognosis depends on the underlying cause

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

 Urobilinogen and urobilin in icteric stage Urobilin is positive and urobilinogen may be negative in cholestatic hepatitis In AIH, the directive bilirubin and indirective bilirubin

Prothrombin time may be prolonged especially in fulminant hepatitis

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

 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

 Ultra-sound examination Liver biopsy Other laboratory examination Blood routine Urine routine