HAV, HBV NonA-NonB: HCV, HDV, HEV Hepatitis Viruses HAV, HBV NonA-NonB: HCV, HDV, HEV

Hepatitis Hepatitis (plural hepatitides) is an inflammation of the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar meaning liver, and suffix -itis, meaning "inflammation. Clinical manifestations of hepatitis are virtually the same.

Hepatitis The condition can be self-limiting (healing on its own) or can progress to fibrosis (scarring) and cirrhosis. Acute: < 6 months Chronic: > 6 months Causes: Hepatitis or some other viruses. Alcohol, certain medications and plants.

HAV Disease Hepatitis A (Infectious hepatitis) Important properties Typical enterovirus (enterovirus72) classified in Picornavirus. Recently in new genus: Hepatovirus. Single stranded RNA genome, positive sense, Non - enveloped icosahedral nucleocapsid, 27-32 nm

HAV replicates in the cytoplasm of the cell One serotype Humans and chimpanzees are the only natural hosts

Replicative cycle A positive strand RNA: Genome replication occurs by synthesis of a complementary negative strand which then serves as the template for the positive strands which are needed both for replication and protein synthesis. Against other Picornavirus, it requires an intact eukaryote initiating factor 4G (eIF4G) of the cell for the initiation of translation.

Resistancy Resistant to: 60 c for 1 hour Acid (pH=1) for 2 hours Ether 20% for several hours Fresh and salt water for months

Transmission & Epidemiology Transmitted by fecal-oral (water, food, flies) and parenteral route. Virus in feces 2 weeks before the symptoms. So quarantine of patients is ineffective. In developing countries and regions with poor hygiene standard, children are the most frequently infected group. 40% of all acute viral hepatitis is caused by HAV.

Transmission & Epidemiology As incomes rise and access to clean water increases, the incidence of HAV decreases. Mostly seen in susceptible young adults often during trips to countries with a high incidence or contact with infectious persons.

Pathogenesis HAV replicates in gasterointestinal tract epithelial cells and spreads to the liver via the blood. Very low level of viremia Hepatocytes are infected. HAV infection of cultured cells produces no cytopathic effect. Immune attack on the hepatocytes plays no role in pathogenesis (A difference with HBV).

The level of viremia is low and chronic infection does not occur. The infection cannot be distinguished pathologically from other hepatitis infections. Acute hepatitis A infection can vary from being an asymptomatic condition to being severe enough to cause fulminant (sudden and severe) liver failure.

Clinical findings (HAV) Incubation period: 2-6 weeks, average 1 month Usually resolve spontaneously in 2-4 weeks. No chronic infection or chronic liver disease 10-15% of patients might experience a relapse of symptoms during the 6 months after acute illness. Case fatality rate: 0.5% mainly in elder people.

Clinical findings (HAV) No clinical signs and symptoms in over 90% of infected children. Fever Anorexia (loss of appetite) Nausea Vomiting Jaundice (icterus) Fatigue Abdominal pain

Clinical findings (HAV) Itching weight loss Hepatomegaly Bile removed from blood and excreted in urine, giving it a dark amber colour. Feces light in colour due to lack of bilirubin in bile.

Jaundice

Clinical findings (HAV) > 80% of adults show symptoms and majority of children having asymptomatic infections. Alaninamino transferase (ALT) = Alaninamino transferase level is much higher than normal: a non-specific sign of HAV infection. ALT comes from the liver cells damaged by the virus.

Immunity Immune response is initially IgM antibody detectable at the time jaundice appears. The appearance of IgM is followed 1-3 weeks later by the production of IgG antibody which provides lifelong protection.

Laboratory diagnosis Samples: Blood, Stool Cell culture in Resus monkey cells but no CPE Measuring IgM and IgG titer, especially IgM antibody in the blood. The liver enzyme alanine transferase (ALT). PCR

Interpretation of Diagnostic Tests for HAV Infection HAV IgG             HAV IgM IgM             Interpretation                                                                                              Positive              Positive              Acute HAV infection                                                                                       Negative             Positive              Acute HAV infection (earlier phase than above)                                              Positive              Negative             No acute HAV infection - person has protective immunity                                 Negative             Negative            No acute HAV infection and no immunity – at risk for getting HAV in future    

Treatment A self-limited disease (Resolves itself spontaneously) No antiviral therapy Rest, avoid fatty food and alcohol

Prevention Vaccination (by injection): protection starts 2-4 weeks after vaccination. The second booster is given six to twelve months later. Passive immune prophylaxy Sanitation by using Killing methods: Boiling for 1 min Sodium hypochlorite for 5 min Chlorin treatment (drinking water)

HBV A member of hepadenavirus 42-nm enveloped virion with an icosahedral nucleocapsid Partially double-strand circular DNA genome

HBV 42-nm virions, 22-nm spheres, long filaments 22 nm wide

Antigenes and fragments HBsAg (important both in diagnosis and immunization) DNA-dependent DNA polymerase 3 different types of particles: HBs Ag (42-nm virions, 22-nm spheres, long filaments 22 nm wide) HBcAg (Core antigen ) HBe Ag (an indicator of transmissibility)

Serotypes based on HBsAg A group-specific antigen, ‘a’ and 2 sets of exclusive epitopes, d or y and w or r leading to 4 serotypes: adw, adr, ayw, ayr which are useful in epidemiologic studies. a y d W  adw w  ayw r  adr r  ayr

HBV Genotypes Eight genotypes (A-H) according to overal nucleotide sequence variation of the genome differing by at least 8% of their sequence. They have a distinctive geographical distribution used in tracing the evolution and transmission of the virus. Differences between genotypes affect the disease severity, course and likelihood of complications.

Humans are the only natural host of HBV

Replicative cycle DNA polymerase synthesize the missing portion of DNA --- Fully double-strand circular DNA in nucleus --- Some DNA copies integrates into hepatocyte DNA /// Some DNA copies serves as a template for mRNA synthesis --- mRNA functions both in protein synthesis and template for the DNA minus strand (by RNA-dependent DNA polymerase) --- DNA minus strand serves as template for plus strand.

Clinical finding Incubation period: 2-3 months The acute disease is similar to that of HAV. Symptoms in HBV tend to be more severe than HAV. Most chronic carriers are asymptomatic.

Pathogenesis Entering HBV the blood --- infecting hepatocytes ---necrosis and inflammation (Immune attack against viral antigens on infected hepatocytes).

Chronic carriers (carriers of HBsAg ) are asymptomatic. Chronic hepatitis. Hepatitis with no apparent liver clinical involvement. Fulminant hepatitis. Occurrence: 1-2%, Highly and fulminant necrosis of lever paranchim. 60-90% is lethal. (Increase of Alaninamino transferase (ALT or SGPT) and Aspartat transferase (AST or SGOT).)

Chronic persistent hepatitis Chronic persistent hepatitis. (probably due a persistent infection of hepatocytes mediated DNA integrated into cell DNA). Largeness of liver, increase of liver enzyms. Chronic active hepatitis may leading to chronic necrosis of liver cells and paranchim (cirrhosis), hepatocellular carcinoma and death.

Transmission & Epidemiology Blood is Most important way of transmission. In addicts using intravenous drugs. Sexual transmission. Mother to child during birth or breast feeding. Immunization reduces the incidence.

Laboratory diagnosis Samples: Blood is the best. Liver biopsy Cell culture and CPE: Not affective ELISA and Immunoassay:

Laboratory diagnosis Immunoassay for HBs Ag HBsAg during the incubation period and mostly during the prodome and acute disease. Prolonged presence of HBsAg indicates carrier state and the risk of chronic hepatitis.

Laboratory diagnosis Windows phase: no HBsAg and HBsAb but HBcAb HbeAg: During incubation period and is present during prodrome and early acute disease (an indicator of transmissibility). HBeAb indicates low transmissibility. DNA polymerase during incubation and early in the disease but assay not available in clinical lab.

Treatment & Prevention Alpha interferon Lamivudine (inhibits hepatitis B viral DNA synthesis) Baraclude (inhibiting hepatitis B viral DNA synthesis) Rest, combined with a high protein/high carbohydrate diet to repair damaged liver cells. Prevention by using vaccine and hyperimmune globulin No one with a history of hepatitis (of any type) should donate blood.

NON-A, NON-B hepatitis viruses HCV Distributed worldwide The most major agent of Non-A, Non-B An enveloped single-strand RNA virus (a flavivirus). Incubation period: an average of 2 months No immunity

HCV

HCV It has infected 200 million people worldwide. The leading cause of cirrhosis, a common cause of hepatocellular carcinoma The leading reason for liver transplantation. Coinfection with HIV is common. Prevalence is higher in some countries in Africa and Asia. Egypt has the highest serovalence for HCV (20% in some areas).

Transmission The way of transmission is the same as HBV: Unsterilized injection equipment Transfusion of unscreened blood Sexual contacts

Pathogenesis It is often asymptomatic but progress to scarring of the liver (fibrosis) and advanced scarring (cirrhosis) and complicated into liver cancer after many years. Persistent infection are common and most patients develop chronic HCV lasting more than 6 months.

Clinical finding Generalized signs and symptoms is the same as HBV. Symptoms suggestive of liver disease are typically absent until substantial scaring of the liver has occurred.

HCV Up to 80% of cases go to chronic forms tend to cause cirrhosis (20-50%) or hepatocellular carcinoma (5-25%). Mild infection (only 25%) show jaundice. Most cases are asymptomatic

HCV genotypes There are at least 6 genotypes (HCV-1 to HCV-6) - The more common in the middle east and Africa is genotype 4. HCV genotypes are related with human races.

Diagnosis It is based on serologic methods (ELISA) for detecting HCV antibodies. It can detect 80% of patients within 15 weeks after exposure and > 97% by 6 months. As immunocompromised individuals never develop antibodies to the virus, RNA testing (PCR) should be considered when antibody testing is negative.

Diagnosis Elevated liver enzymes, alanin amino transferase (ALT) = (sGPT) and leucine amino transferase (LAT)= (sGOT)

Treatment Interferon Ribavirin - 50% of chronic cases do not respond to therapy. - There is a small chance of clearing the virus spontaneously in chronic HCV carriers (0.5% - 0.74%).

HEV An enterically transmited virus Nonenveloped, single-stranded RNA virus (from calcivirus). Diagnosis is serologic (ELISA) based on IgM and IgG No antiviral agent for treatment

HDV (Delta agent) Single-stranded circle RNA RNA genome surrounded by an envelope composed of HBsAg. A defective virus as its genome does not code for its own envelope protein. HDV can only replicate in HBV-infected cells. Delta antigen is a distinctive determinant present in this virus but not in HBV.

HDV HDV + HBV infection tends to be a fulminant hepatitis. Transmission the same as HBV A chronic carrier state can occur. Infection can be detected by the appearance of IgM to delta antigen. No treatment No vaccine

HGV A Flavivirus Single stranded RNA, enveloped Transmission by blood products Not detected as epidemic in Iran Lab detection is normally by PCR. Not cultivable on cell culture No treatment or vaccination