H EPATITIS

H EPATITIS VIRUSES At least 6 viruses HAV HBV HCV HDV HEV HGV?

H EPATITIS V IRUSES hepatitis alphabet of viruses includes at least six viruses, A through E, and G Although the target organ for each of these viruses is the liver, and the basic hepatitis symptoms are similar, they differ greatly in their structure, mode of replication, mode of transmission, and in the time course and sequelae of the disease they cause. : Hepatitis A virus (HAV) Hepatitis B virus (HBV) Hepatitis C virus(HCV) Hepatitis D virus (HDV Hepatitis E virus (HEV)

H EPATITIS VIRUSES / HEPATITIS Liver damage Icteric symptomes Jaundice Release of liver enzymes

H EPATITIS V IRUSES Hepatitis A, which is sometimes known as infectious hepatitis, (1) is caused by a picornavirus, a ribonucleic acid (RNA) virus; (2) is spread by the fecal-oral route; (3) has an incubation period of approximately 1 month, after which icteric symptoms start abruptly; does not cause chronic liver disease; rarely causes fatal disease.

S PREAD OF HAV WITHIN THE BODY

H EPATITIS A VIRUS /E PIDEMIOLOGY Seropositivity rate of adults in various countries: Sweden13% USA41-44% Yugoslavia97% Taiwan88% Turkey 65-above 95%

T IME COUR SE OF HAV INFEC TION

H EPATITIS A VIRUS /L ABORATORY DIAGNOSIS Time course of the clinical symptomes Identification of a known infected source Specific serologic tests anti-HAV IgM by ELISA

H EPATITIS A VIRUS /T REATMENT, P REVENTION & CONTROL Fecal-oral spread Prophylaxis Immune serum globulin Before or early in the incubation period: 80-90% effective in preventing clinical illness Vaccine: killed HAV vaccine (FDA appr) For use in children or adults at risk for infection

H EPATITIS B VIRUS Hepa dna Hepa dna viruses Infect : liver, kidneys, pancreas Only humans and chimpanzees

H EPATITIS B VIRUS /S TRUCTURE Small Envelopped DNA genome Several unusual properties: Small (3200 bases) -circular-partly double-stranded DNA Encodes a reverse transcriptase Replicates through an RNA intermediate

H EPATITIS B previously known as serum hepatitis, (1) is caused by a hepadnavirus with a deoxyribonucleic acid (DNA) genome; (2) is spread parenterally by blood or needles, by sexual contact, and perinatally; (3) has a median incubation period of approximately 3 months, after which icteric symptoms start insidiously; (4) is followed by chronic hepatitis in 5% to 10% of patients; and (5) is causally associated with primary hepatocellular carcinoma (PHC). More than one third of the world's population has been infected with HBV, resulting in 1 to 2 million deaths per year. The incidence of HBV is decreasing, however, especially in infants, because of the development and use of the HBV subunit vaccine.

U NIQUE F EATURES OF H EPADNAVIRUSES Virus has enveloped virion containing partially double- stranded, circular DNA genome. Replication is through a circular RNA intermediate. Virus encodes and carries a reverse transcriptase. Virus encodes several proteins (HBsAg [L, M, S]; HBe/HBc) that share genetic sequences but with different in-frame start codons. HBV has a strict tissue tropism to the liver. HBV-infected cells produce and release large amounts of HBsAg particles lacking DNA. The HBV genome can integrate into the host chromosome.

H EPATITIS B VIRUS /S TRUCTURE Virion: Dane particule, 42nm in diameter Unusually stable for an envelopped virus Resist treatment with : ether, a low pH,transmission Freezing, Moderate heating

H EPATITIS B VIRUS /S TRUCTURE Virion: Dane particule, 42nm in diameter include: a polymerase Reverse transcriptase activity Ribonuclease activity HBcAg HBsAg, 3 forms: L>M>S glycoproteins, contains “a” determinant (goup- specific), and “d” or “y” and “w” or “r”, type-specific determinants

H EPATITIS B VIRUS /R EPLICATION “Unique!” Replicates through an RNA intermediate and produces and releases antigenic decoy particules

H EPATITIS B VIRUS The virus has RNA-dependent DNA polymerase: (Reverse transcriptase)

H EPATITIS B VIRUS A circular positive-strand RNA intermediate is first synthesized by: cell’s DNA dependent RNA polymerase RNA-dependent DNA polymerase: a negative strand DNA is formed positive RNA degragated Positive strand DNA is initiated but stops when the genome and the core enveloped RESULT: partially double stranded DNA

H EPATITIS B VIRUS /P ATHOGENESIS &I MMUNITY HBV can cause: Acute or Chronic, Symptomatic or, Asymptomatic disease...

H EPATITIS B VIRUS /P ATHOGENESIS &I MMUNITY “It’s determined by the person’s immune response to the infection”

H EPATITIS B VIRUS /P ATHOGENESIS &I MMUNITY HBsAg and HBeAg in the blood: ongoing active infection The major source of infectious virus is blood Semen Saliva Milk Vaginal & menstrual secretions Amniotic fluid

H EPATITIS B VIRUS /P ATHOGENESIS &I MMUNITY Infants & young childrens are less able to resolve the infection ~90% infected perinatally become chronic carriers

H EPATITIS B VIRUS /E PIDEMIOLOGY asymptomatic carriers foster the spread of the virus Routes of spread: sexual, parenteral, and perinatal

H EPATITIS B VIRUS /E PIDEMIOLOGY Transmission: Contaminated blood, blood components Needle sharing Acupuncture Ear piercing Tattooing Very close personel contact The exchange of semen, saliva, vaginal secretions (e.g., sex, childbirth)

H IGH -R ISK G ROUPS FOR H EPATITIS B V IRUS I NFECTION People from endemic regions (i.e., China, parts of Africa, Alaska, Pacific Islands) Babies of mothers with chronic hepatitis B virus Intravenous drug abusers People with multiple sex partners, homosexual and heterosexual Hemophiliacs and other patients requiring blood and blood product treatments Health care personnel who have contact with blood Residents and staff members of institutions for the mentally retarded Hemodialysis patients and blood and organ recipients

H EPATITIS B VIRUS /C LINICAL SYNDRONNES Chronic infection 5-10% of people with HBV infections

H EPATITIS B VIRUS /C LINICAL SYNDRONNES Primary hepatocellular carcinoma 80% of all cases of chronic HBV inf. One of the three most common cause of cancer mortality in the world May become the first vaccine- preventable human cancer Latency period: 9 to 35 years

I NTERPRETATION OF SEROLOGIC MARKERS OF HEPATITIS B VIRUS INFECTION H EPATITIS B VIRUS /L ABORATORY DIAGNOSIS I NTERPRETATION OF SEROLOGIC MARKERS OF HEPATITIS B VIRUS INFECTION Serologic reactivity Disease state Healthy state EarlyEarly acute AcuteChronicLate acute Resolved vaccinat ed Anti-HBcAnti-HBeAnti-HBsHBeAgHBsAg Infectious virus / /

HB E A G Secretory form of HBcAg Indicates viral replication and infectivity In some chronic infections HBV DNA is high No HBeAg Because of a mutation in core promoter or precore region which encodes HBcAg +mutations in core region enhances severity, increase risk of cirrhosis

A CUTE INFECTION HBsAg AntiHBc-IgM Immunity: Anti-HBs ≥10IU/ml

HBV INFECTION : NAT 1-HBV DNA PCR (real-time PCR: quantitation:IU/ml) -staging the disease -prognosis detection -monitoring therapy 2-HBV Genotyping: Antiviral Resistance detection

H EPATITIS B VIRUS /P REVENTION &C ONTROL Screening donated blood HBsAg, anti-HBc Avoiding intimate personal contact with HBsAg (+)’s Avoiding the lifestyles that facilitate the spread of the virus (High risk groups Vaccination

H EPATITIS B VIRUS /P REVENTION &C ONTROL Universal blood and body fluid precautions (refer to HIV and retroviruses lesson)

P REVENTION, AND C ONTROL Transmission of HBV in blood or blood products has been greatly reduced by screening donated blood for the presence of HBsAg and anti-HBc. Additional efforts to prevent transmission of HBV consist of avoiding sex with a carrier of HBV and avoiding the lifestyles that facilitate spread of the virus. Household contacts and sexual partners of HBV carriers are at increased risk, as are patients undergoing hemodialysis, recipients of pooled plasma products, health care workers exposed to blood, and babies born of HBV- carrier mothers.

P REVENTION, AND C ONTROL Vaccination is recommended for infants, children, and especially people in high-risk groups For newborns of HBsAg-positive mothers and people accidentally exposed either percutaneously or permucosally to blood or secretions from an HBsAg-positive person, vaccination is useful even after exposure. Immunization of mothers should decrease the incidence of transmission to babies and older children, also reducing the number of chronic HBV carriers. Prevention of chronic HBV will reduce the incidence of PHC. is not readily inactivated by detergents.

T HE HBV VACCINES subunit vaccines. The initial HBV vaccine was derived from the 22- nm HBsAg particles in human plasma obtained from chronically infected people. The current vaccine was genetically engineered and is produced by the insertion of a plasmid containing the S gene for HBsAg into a yeast, Saccharomyces cerevisiae. The protein self- assembles into particles, which enhances its immunogenicity.

T HE HBV VACCINES The vaccine must be given in a series of three injections, with the second and third given 1 and 6 months after the first. More than 95% of individuals receiving the full three-dose course will develop protective antibody. The single serotype and limited host range (humans) help ensure the success of an immunization program.

U NIVERSAL BLOOD AND BODY FLUID PRECAUTIONS are used to limit exposure to HBV. It is assumed that all patients are infected. Gloves are required for handling blood and body fluids; wearing protective clothing and eye protection may also be necessary. Special care should be taken with needles and sharp instruments. HBV-contaminated materials can be disinfected with 10% bleach solutions

H EPATITIS C AND G VIRUSES HCV was identified by molecular biologic means in 1989 Predominant cause of NANBH virus infections Major cause of post-transfusion hepatitis (before routine screening of the blood supply for HCV)

H EPATITIS C VIRUS HCV > (17x 10 7 ) carriers in the world but Transmission similar to HBV but “Greater potential for establishing persistent, chronic hepatitis” Cirrhosis HCC

H EPATITIS C VIRUS /S TRUCTURE & R EPLICATION “HCV has never been isolated” “Only member of the Hepaciviridae” (family: Flaviviridae) Enveloped Positive-sense RNA Encodes 10 proteins (2 glycoproteins, E1, E2) 6 groups of variants (clades), genotypes..

H EPATITIS C VIRUS /P ATHOGENESIS Cell-mediated immunopathology is responsible mainly for producing the tissue damage Antibody to HCV is not protective! Immunity to HCV may not be lifelong

H EPATITIS C VIRUS /E PIDEMIOLOGY Is transmitted primarily in infected blood and sexually Almost all (>90%) HIV infected individuals who are/were IVDUs are infected with HCV Almost 20 % of Egyptian blood donors are (+)

H EPATITIS C VIRUS /C LINICAL SYNDROMES 3 types of diseases Acute hepatitischronic persistant inf. Cirrhosis (15% recovery) (70%) (15%)

H EPATITIS C VIRUS /C LINICAL SYNDROMES Acute HCV infectionsimilar to acute HAV/HBV, Inflammatory response is less intense Symptoms milder >80% asymptomatic

H EPATITIS C VIRUS /L ABORATORY DIAGNOSIS Anti-HCV with ELISA Seroconversion within 7 to 31 weeks of infection HCV antigen with ELISA HCV RNA with real-time PCR Genotyping

H EPATITIS D VIRUS ~ 15 million people are infected with HDV in the world Cause of 40% of fulminant hepatitis infections Unique Uses HBV and target cell proteins to replicate and produce its one protein “a viral parasite” HBsAg is essential for packaging the virus

H EPATITIS D VIRUS /S TRUCTURE &R EPLICATION ssRNA genome ~ 1700 nucleotides Rod shaped (circular) Virion size ~ HBV Delta Ag surrounded by HBsAg containing envelope

T HE DELTA HEPATITIS VIRION

H EPATITIS D VIRUS /P ATHOGENESIS Similar to HBV : Spread in blood, semen, and vaginal secretions It can replicate and cause disease only in people with active HBV infections coinfected A person can be coinfected with HBV & HDV, or superinfected A HBV carrier can be superinfected with HDV Replication of HDV results in cytotoxicity and liver damage Unlike HBV, damage to the liver occurs as a result of the directc cytopathic effect of the delta agent combined with the underlying immunopathology of the HBV disease

H EPATITIS D VIRUS /E PIDEMIOLOGY Worlwide distribution Endemic in southern Italy, the Amazon Basin, parts of Africa, and the Middle East Spread by the same routes as HBV

H EPATITIS D VIRUS /C LINICAL SYNDROMES Increases the severity of HBV infections > fulminant hepatitis than other H. viruses

H EPATITIS D VIRUS /L ABORATORY DIAGNOSIS Ag, Ab, with ELISA or RIA HDV RNA

D ELTA VIRUS The most unusual mode of replication Circular single stranded RNA Uses the host cell DNA dependent RNA polymerase in the nucleus Needs the presence of HBV A defective virus HBsAg is necessary for packaging the virus

H EPATITIS D VIRUS /T RE -P RE -C O No known specific treatment Prevention of HBV HBV vaccine

H EPATITIS E VIRUS E-NANBH Enteric/epidemic Non-A, Non-B hepatitis Predominently spread by the fecal-oral route, esp. in contaminated water Worlwide Problematic in developping countries

H EPATITIS E VIRUS Epidemics in India, Pakistan, Nepal, Burma, North Africa, Mexico Symptoms and course similar to those of HAV Cause only acute disease Mortality rate associated with HEV disease is x10 times that associated with HAV disease (~1-2%)

H EPATITIS E VIRUS Mortality rate associated with HEV disease is x10 times that associated with HAV disease (~1-2%) Serious in pregnant women: Mortality rate of approximately 20%

O THER VIRUSES THAT CAN CAUSE HEPATIC INFLAMMATION INCLUDE Epstein-Barr virus (EBV); herpes simplex virus (HSV); mumps, rubella, rubeola, varicella-zoster virus; yellow fever virus; coxsackie B virus, and adenovirus.

VIRUSES BEYOND A TO E Approximately 15% to 17% of hepatitis infections remain unexplained. Acute hepatitis and chronic hepatitis occur sporadically, after transfusion and in organ transplant recipients. Some such cases result in the development of fulminant liver failure. The causative agents for non-A to E hepatitis continue to be sought.

VIRUSES BEYOND A TO E Candidate viruses include hepatitis F virus (HFV), HGV, TTV, and SEN virus. HFV was initially identified as a putative hepatitis virus spread by the fecal-oral route; however, there is insufficient evidence to corroborate this, and the identity of HFV is in doubt. Two viral agents related to hepatitis have been identified and designated. HGV is also known as hepatitis-GB virus (HGBV) (so named after the initials of the patient from whom the virus was isolated). There is considerable homology between HGV and HGBV. Three different viruses were isolated and designated GBV-A, GBV-B, and GBV-C. The role of HGV and GBV-C in human disease, if any, remains unestablished.

D IFFERENTIAL D IAGNOSIS OF A CUTE H EPATITIS Epstein-Barr virus Cytomegalovirus Herpes simplex virus Yellow fever Leptospirosis Q fever Human immunodeficiency virus Brucellosis Lyme disease Syphilis

Y ELLOW FEVER enzootic in central Africa, Central America, and South America. More than 90% of cases occur in Africa. Yellow fever is characterized by an incubation period (3 to 7 days) much shorter than that of hepatitis A, B, and C viruses. Patients can present with a severe hepatitis. Yellow fever should be suspected in the recent traveler to enzootic areas who did not receive adequate immunization. The mortality rate in yellow fever approximates 20%.

LEPTOSPIROSIS A zoonosis Patients with infection present with an abrupt onset of fever, chills, myalgias, and headache They may have marked jaundice. On physical examination, prominent conjunctival suffusion is often noted. Leukocytosis, which is uncommon in acute viral hepatitis, may be prominent and together with urinary findings of proteinuria, hematuria, and anuria should raise the suspicion of leptospirosis. The serum creatine phosphokinase is elevated in 50% of patients. Marked jaundice accompanied by renal dysfunction in a febrile patient with leukocytosis should raise the possibility of Weil's syndrome, a severe form of leptospirosis.

Q FEVER is caused by the rickettsial agent Coxiella burnetii Epidemiologic features linking exposure to farm or wild animals and the finding of unique hepatic granulomas (fibrin-ring granulomas are suggestive but not pathognomonic) should lead the clinician to suspect Q fever.