Chronic Viral Hepatitis:

Associate Prof Dr Meltem ErgunYeditepe UniversityDepartment of Gastroenterology

Objective1. To identify the etiologic agents of chronic viral

hepatitis2. Know the

Pathophysiology, Clinical presentation

Diagnosis, Evaluation and Management of chronic viral hepatitis

Clinical Terms

• Hepatitis: inflammation of liver; presence of inflammatory cells in the liver

• Acute Viral Hepatitis: symptoms last less than 6 months• Chronic Hepatitis: Inflammation of liver for at least 6 months• Cirrhosis: a late stage of progressive hepatic fibrosis

characterized by distortion of the hepatic architecture and the formation of regenerative nodules.

• Fulminant Hepatitis: severe impairment of hepatic functions or severe necrosis of hepatocytes in the absence of preexisting liver disease

Acute viral hepatitisetiologic agents

Acute viral hepatitis

• Hepatitis A• Hepatitis B• Hepatitis C• Hepatitis D• Hepatitis E

Hepatitis A• Common cause of acute hepatitis• Single-stranded, positive-sense, linear RNA enterovirus (Picornaviridae) • Transmission fecal-oral route; Contaminated water and food• The incubation period of hepatitis A virus is 2-7 weeks,• AST & ALT levels usually return to reference ranges over 5-20 weeks.• High risk Travellers: vaccinations; passive immunoglobins given to

those exposed• Mild self-limited disease and confers lifelong immunity to hepatitis A

virus. Chronic infection with hepatitis A virus does not occur. • HAV: IgM anti-HAV: positive at the time of onset of symptoms; results

remain positive for 3-6 months after the primary infection• Treatment: supportive

Hepatitis E

• Hepatitis E virus (HEV) RNA virus of the genus Hepevirus

• Enterically transmitted infection; fecal-oral route, typically self-limited

• Most outbreaks occur in developing countries.• Symptoms of acute hepatitis• Incubation period of hepatitis E virus is 2-9 weeks• Case fatality rate is 4% Pregnancy mortality ↑

Clinical Evaluation: Acute Viral Hepatitis

1. Prodromal phase:• Patients experience anorexia, nausea, vomiting, alterations in taste, arthralgias, malaise,

fatigue, urticaria, and pruritus. Some develop an aversion to cigarette smoke.• When seen by a health care provider during this phase, patients are often diagnosed as

having gastroenteritis or a viral syndrome.

2. Icteric Phase• Jaundice, Patients may note dark urine, followed by pale-colored stools.• In addition to the predominant gastrointestinal symptoms and malaise, patients become

icteric and may develop right upper quadrant pain with hepatomegaly.

Severe cases may result in Fulminant Hepatitis:1.Hepatic Encephalopathy: B/L asterixis, palmar erythema2.Hepatorenal syndrome3.Bleeding diathesis

Chronic Hepatitis

• HBV• HCV• HDV

Hepatitis: B & D

Hepatitis B(HBV)--EPIDEMIOLOGY

• HBV is a DNA virus that belongs to the hepadnavirus family.• 1/3 of population of the World has had hepatitis B infection. • 400 million people are chronic HBV carriers.• HBV is the cause of 60% to 80% of worldwide

Hepatocellular Carcinoma(HCC).• 500,000 to 1 million deaths worldwide are attributed to it.• 5% to 10% of all liver transplants are attributed to HBV.• In Turkey %80 transplants are attributed to HBV.

Risk Groups

• IV drug users• People receiving multiple blood transfusions• Sexual promiscuity• People in contact with HBV carriers• Travelers to endemic areas of South America,

Southern Asia, and Africa• Resident and employees of residential care facilities• Health Care Workers

Pathophysiology

Transmission 3 main ways:

• Parenterally/percutaneous route----IV Drug Users, needle sticks, Hemodialysis patients

• Sexually

• Vertical/ Perinatal route (TURKEY)

SerologyHBsAg surface antigen• Present in acute or chronic infection• Detectable 1 to 2 weeks after infection

HBeAg• Appears shortly after HBsAg• Indicates viral Replication and Infectivity

HBsAB(Anti-HBS)• Present after vaccination or clearance of HBsAg(Usually 1 to 3 months)• Indicates immunity to HBV

Hb core Antibody (IgM anti-Hbc or IgG anti-HBc)• Only Serological marker of HBV during "Window Period"

Hbs ag+Hbs ag+

HBV DNA <2000

Hbe ag -

HBV DNA >2000

Inactive carrier every 6 months ALT AFP USG HBV DNA

Chronic hepatitis B bx and treatment

HBV DNA >2000

Hbe ag +Immune tolerant phase

Clinical PresentationAcute Hepatitis B - less than 6 months; Based on significant aminotransferase activity due to

necro inflammatory injury• Symptoms are often non-specific symptoms such as myalgia, malaise , nausea, fatigue ,

pruritus, abdominal pain, RUQ, jaundice• Fulminant Hepatitis--Acute HBV results in Liver Failure

Chronic Hepatitis B - greater than 6 months; Based on grade, stage, and etiology. Fibrosis and Necroinflammatory processes; can last for decades

• Immune tolerant--High viral replication, NL liver enzymes, low inflammation and fibrosis. Seen in children or those affected early in life.

• Immune active--High Liver enzymes and High HBV DNA and HBeAg, Active Replication• Carrier State with low replication

• Seroconversion from HBeAg to HBeAB• Low HBV levels, NL liver enzymes, Reduced Liver inflammation• Low risk for developing of HCC

Clinical Presentation cont.

Chronic HbeAg negative • HBV DNA high, Liver enzymes high, No HbeAg• Seen in late phase of HBV

Resolution• Viral clearance of HBV DNA

Diagnosis

• Serology

• Liver Chemistry tests• AST, ALT, ALP, and total Bilirubin

• Histology--Immunoperoxidase staining

• HBV Viral DNA--Most accurate marker of viral REPLICATION

• Liver Biopsy--to determine grade(Inflammation) and stage(Fibrosis) in chronic Hepatitis

Progression

• Incubation Period: 30-180 days

• Acute HBV Infection: 90% resolve by themselves; less than 1% develop fulminant hepatitic failure

• Chronic HBV Infection: 2-10% progress to chronic state• 90% in children less than five progress to chronic state• Risk of Liver Cirrhosis: 5 year accumulation risk of 8% to 20%• 5% to 10% of people progress to HCC with or without preceding

cirrhosis; less than 5% achieve a chronic carrier state

TreatmentNucleoside Analogues -- Lamivudine, Entecavir,

Telbivudine

Method of action is the inhibition of viral reverse transcriptase

• WEAK AGENTS:• Lamivudine

• Dose : 100 mg PO q daily• Good for reducing the risk of progression

to hepatic decompensation in patients with cirrhosis or advanced fibrosis

• Pregnancy category B--Not teratogenic in animal studies and successful use with pregnant women

• Problem: High rates of resistant mutations

• Telbivudine• Dose: 600mg q daily• Worse resistant profile than Entecavir

Strong Agents:•Entecavir – 1st line

0.5 to 1mg POvery effective; low resistance and greater than 90%  HBV DNA clearance rate in HBeAG positive Px's.more effective than lamivudine

•Tenofovir:Dose: 300mg qdHighly effective with low resistanceWell tolerated

Interferon: Not very effective in Genotype B

Prophylaxis

HBV Vaccine• Indicated for everyone and especially those in high risk groups

• IM injection at 0,1,6 months in infants and adults• Response greater than 90% after 3rd dose

HBV Pregnant Mothers• Give 1st dose of Hip B vaccine and Hip B Immunoglobulin(HBIG) o.5 ml within 12 hours of birth.

• 2nd dose at 1 month, 3rd at 6 months• Recheck at 12 months for active infection• 95% lifetime immunity• Not Done---leads to 90% chronic HBV• Transmitted through birth canal during birth or through umbilical cord.

Others i.e. those receiving a needle stick• Should receive 0.04 to 0.7 ml/kg of HBIG and 1st dose vaccine within 48 and no later than a

week.

Transplant

• Last resort for those with advanced Liver Disease and HCC due to infection

HEPATITIS D

Transmission• Only as co-infection with acute HBV or with superinfection in chronic

HBV carrier• Requires outer envelope of HBsAG for replication and transmission• Can progress to chronic disease• Incubation Period 30to 150 days

Serology• Hepatitis D antibody (Anti-HDV)

• Indicates HDV superinfection• Ab not always present in acute infection---requires repeat testing

HEPATITIS D

Risk Factors - Same high risk groups as those for Hip B Prevention - Avoidance of Hip B and/or Hip B vaccine DX - HDV antigen in serum or finding Ab to HDV antigen

Clinical• Coinfection-self limited• Superinfection-acute HBV carriers present with severe acute hepatitis infection w/ increased risk

for HDV infection. Fatality Rate - 2% to 10%

Cirrhosis – Fast

TX:IFN-alpha

A hepatitis panel is ordered for a 27 year old female as part of a routine workup for abdominal pain.

Results of serological testing a negative for HBeAg - and HBsAg -,

HBsAb + and IgG HBcAb +. The patient has been exposed to Hep B.a.Patient has recoveredb.Patient is in acute infective disease statec.Window periodd.Chronically infectede.Patient was never infected

Imaging Studies• No specific imaging studies needed for diagnosis• Obtain the appropriate diagnostic imaging studies (eg, ultrasound, CT) if the

differential diagnosis favors gallbladder disease, biliary obstruction, or liver abscess.

Liver biopsy usually in cases of: o The diagnosis is uncertain. o Other coinfections or disease may be present. o The patient is immunocompromised. o Asses severity of chronic hepatitis B or chronic hepatitis C.

Histologic FindingsLymphocytic infiltration, moderate degrees of inflammation and necrosis, and

portal or bridging fibrosis are noted. Regenerative nodules are seen in patients with cirrhosis.

•LFT: Elevation of serum transaminases not diagnostic, but usefula)ALT elevated more than ASTb)Acute Hepatitis: ALT > 1000c)Chronic HCV: ALT is generally x1,5-2 ULN

* Urine analysis: presence of bilirubin. * Serum bilirubin: Total bilirubin may be elevated in infectious hepatitis. Bilirubin levels higher than 30 mg/dL indicate more severe disease. * Alkaline phosphatase: if elevated significantly, consider abscess or biliary obstruction. * Prothrombin time (PT) if prolonged impaired synthetic function of the liver. * BUN & serum creatinine decreased renal function suggests fulminant hepatic disease. * Serum ammonia in patients with AMS or other evidence of hepatic encephalopathy.* CBC: lymphocytosis

Lab Studies:

Hepatitis C

• Spherical, enveloped, single-stranded RNA virus (Flavivirus genus)

• Incubation period: 7-8 wks• 170 million infected worldwide• Major cause of chronic hepatitis in U.S. • More common in Hispanic, AA population; females

have better outcome• Parenteral Transmission: IV drug users• Most common indication for liver transplantation

Clinical Evaluation: Chronic Hepatitis C

- Occurs after acute Hepatitis in >80% of people with HCV - Some are asymptomatic, or have mild symptoms; others may only

present with late complications (cirrhosis/HCC)- Categorized based on grade of inflammation, stage of fibrosis, and

etiology of disease

Hepatitis C• Usually clinically mild, does not cause significant acute

illness• Fluctuating elevations of AST & ALT• 20% likelihood of developing cirrhosis• 50% likelihood of developing chronic hepatitis• Incubation period: 15-150 days, with symptoms developing

anywhere from 5-12 weeks after exposure.

Diagnosis: HCV

• HCV: Anti-HCV; cannot distinguish acute from chronic infection• may appear 3 – 5 months after infectionPCR: used to detect viral RNA HCV80% of cases: patients are asymptomatic and do not develop icterus.Treatment: Interferon alpha, Ribavirin; PEG-IFNs (better sustained

absorption, a slower rate of clearance, and a longer half-life than those of unmodified IFN)

+protease± polymerase inhibitors (sofosbuvir+simeprevir)

A 61 yo F is brought to the ER, drowsy and disoriented, only able to follow simple commands. On PE, her abdomen is distended and non-tender and she is jaundiced. In her purse, the physician finds prescriptions for peginterferon and ribavirin. When asked to raise her hands, the physician notes a coarse tremor. Lab values show ALT = 93U/L, AST = 89U/L, total bilirubin = 3.1 mg/dL, and ammonia = 124microg/dL. What is the most likely diagnosis?

A. Bleeding esophageal varicesB. Hepatic encephalopathyC. Hepatocellular carcinomaD. Hepatorenal syndromeE. Spontaneous bacterial peritonitis

Other Causes of Hepatitis

• Alcoholic Hepatitis• Drug induced Hepatitis• Autoimmune Hepatitis• Ischemic Hepatitis