Hepatitis

Hepatitis C

(+)ssRNA-enveloped virus in the Flaviridae family and hepacivirus genus Enveloped glycoproteins E1 (gp 31) and E2 (gp31) Replicates in the cytoplasm Culture system for HCV propagation, the replication cycle of HCV is not fully understood. In infected people, the virions of HCV are firmly associated with lipoproteins to form a complex particle called lipoviroparticle (LVP). These LVPs attach to heparan sulfate proteoglycans on the hepatocytes. Transmitted thru blood and blood derived products inflammation of the liver caused by the hepatitis C virus (HCV), which is transmitted by exposure to infected blood; this strain is rarely contracted sexually

Pathogenesis of Hep B

*HBsAg is found in most body fluids including saliva, semen and cervical secretions* The *serum sickness-like rash and arthritis that may precede the development of symptoms and jaundice* appear to be related to circulating *immune complexes* that activate the complement system. Immune complexes also seen in kidney and results in failure *Antibody to HBsAg is protective in acute hepatitis* CTLs cause damage to liver by destroying infected cells --- will see *postnecrotic hepatic cirrhosis* due to necrosis and subsequent fibrosis of hepatocytes HBx proteins interact with tumor supressor gene p53 and play an important role in developing HCC

HEP D

- co-infection with Hep B i. Severe acute disease ii. low risk of chronic infection - worsens HBV

Epidemiology of Hep B

Approx 400 million people worldwide with infection chronic carriers are common in the far East -- 10% of patients with HIV are carriers of HBV -- In U.S.; 1.25 mil people infected Spread vertically, parenterally, Contact with infected Body Fluids and by sexual contact 50% of infections in the U.S. due to sexual contact (common in men who have sex with men, patients on hemodialysis, down syndrome and injection users) Needle-stick transmission is a risk for healthcare workers Strong association btw chronic infection and Hepatocellular carcinoma (HCC)

HEP B

Belongs to hepadnaviridae family Enveloped DNA The viral genome consists of partially double-stranded DNA with a short, single-stranded piece Encodes: surface (envelope) protein (hepatitis B surface antigen [HBsAg]); core (nucleocapsid) protein (hepatitis B core antigen [HBcAg]); DNA polymerase (reverse transcriptase); and HBx protein (a transcriptional activator). Aggregates of HBsAg are often found in great abundance in serum during infection

Hepatitis A (HAV)

Belongs to the picornaviridae family and hepatovirus genus naked capsid, (+)ssRNA virus; icosahedral The RNA is bound to a protein called VPg VP1 is a spike of HAV that bidnds to the α2-macroglobulin receptor on the host cells (*particularly liver cells*) Enter cells via viropexis Only one serotype of HAV Replicates in cytoplasm inflammation of the liver caused by the hepatitis A virus (HAV), usually transmitted orally through fecal contamination of food or water

HEP E

Fecal oral route thru contaminated drinking water. Common with recent travel to India, Africa, Asia, and Central America Minimal person-person transmission Case fatality higher in pregnant women Severity of illness increase with age Avg 40 day incubation (range from 15 - 60)

Diagnosis

HCV antigens not detectable in blood HCV antibody presence can be diagnostic although it may be negative for 1 - 3 wks after clinical onset (acute disease) ELISA, then RIBA (recombinant immune immunoblot assay)

Clinical capsule

Hepatitis A virus (HAV) is the cause of what was formerly termed infectious hepatitis or short-incubation hepatitis. This virus is spread by the fecal-oral route, and outbreaks may be associated with contaminated food or water. The illness is subclinical in up to 50% of infected adults. When symptomatic, there is usually fever and jaundice. Although fatal disease may occur, self-limited illness is the rule. Chronic hepatitis A rarely, if ever, occurs

Clinical capsule of Hep B

Hepatitis B virus (HBV) is the cause of what was formerly known as "serum hepatitis." This name was used to distinguish it from "infectious hepatitis" and reflected the association of this form of hepatitis with needle use or blood transfusion. HBV is usually an asymptomatic or limited illness with fever and jaundice for days to weeks. It becomes chronic in up to 10% of patients and may lead to cirrhosis or hepatocellular carcinoma.

Clinical capsule of Hep C

Hepatitis C is an insidious disease in that it does not usually cause a clinically evident acute illness. Instead, its first manifestation (in 25% of those infected) may be the presence of smoldering chronic hepatitis that may ultimately lead to liver failure. Its transmission is less well understood than for hepatitis A, B, and D, but causes chronicity in more than 85% of infected patients. Hepatitis C was the major cause of posttransfusion hepatitis until a serologic test for screening blood donors was developed.

Diagnosis of HEP A

IgM anti-HAV = active or recent infection IgG anti-HAV = current or past infection

Pathogenesis of HEP A

In through mouth Replicates in intestines (Enteric mucosa) --> Blood --> Liver Go into bile ducts and make way into stool Replication in the liver leads to lymphoid cell infiltration, necrosis of liver parenchymal cells and proliferation of Kupffer cells (macrophages found in liver) CD8+ T-cells damage the hepatocytes while fighting the virus Increased IgG

Manifestations of HEP B

Incubation - as brief as 30 days or as long as 180 days/ Acute HEP B -- i. fatique ii. Loss of appetite iii. nausea and pain iv; increasing cholestasis, and hence clay-colored stools, darkening of the urine, and jaundice. Symptoms can last several months before resolving HBV more severe and prolonged than HAV One important difference between hepatitis A and hepatitis B is the development of chronic hepatitis, which occurs in approximately 10% of all patients with hepatitis B infection, with a much higher risk for newborns (~90%), children (~50%), and the immunocompromised

Manifestations of HEP C

Incubation period is 6 - 12 wks; usually asymptomatic in 75% of cases but result in a chronic carrier state in up to 85% of adult patients anorexia nausea vomiting dark urine jaundice (symptoms usually occur 4-6 weeks after transfusion) -- Cirrhosis and HCC are late sequelae of chronic hepatitis -- Chronic hepatitis C is the leading infectious cause of chronic liver disease and liver transplantation in the United States.

Clinical manifestations of HEP A

Incubation period of 15-45 days (mean 25 days) -- Followed by Fever, Anorexia, Nausea, Pain in the right upper quadrant and within several days, Jaundice Before Jaundice, will notice Dark urine and clay-colored stools Enlarged liver; Elevated serum Aminotransferase and bilirubin levels Recovery occurs in days to weeks 99% of cases are *self-limiting* No chronic infection unlike HEP B & C

Treatment for HEP B

Interferon Lamivudine inhibits the RT. Doesn't cure HBV infection but inhibit viral replication and may reduce viral loads Entecavir Tenofovir: preferred

Treatment and prevention of HCV

Interferon alpha and Ribavirin Screening of blood,organ, tissue donors • High-‐risk behavior modification • Blood and body fluid precautions

Treatment

No specific treatment Supportive care with nutrition and rest Avoid contaminated food or water or infected persons

Prevention

Passive immunization -- Immune serum globulin I. effective if given before or during incubation period of the disease ii. 80 - 90% effective in prevening clinically apparent Hep A Active immunization -- Formalin-killed HAV I. induces antibody titers similar to those of wild-type virus infection, is almost 100% protective, and is now recommended for all children at age 1 and for adults with a high risk of infection. II. Two doses are given 6 to 12 months apart to achieve long-term protection. III. In the United States two inactivated HAV vaccines, HAVRIX (GlaxoSmithKline) and VAQTA (Merck & Co) are currently licensed.

Diagnosis of Hep B

Serum detection of HBsAg and HBV DNA during acute episode of disease The development of anti-HBs is associated with elimination of infection and protection against reinfection. Anti-HBc is detected early in the course of disease and persists in serum for years.

Prevention of Hep B

Similarly, screening pregnant women and treatment of exposed newborns with *hepatitis B immune globulin (HBIG)* and vaccine have reduced vertical transmission HBIG is prepared from sera of subjects who have high titers of antibody to HBsAg, but are free of the antigen itself Safe-sex; avoidance of needlestick injuries or injection drug use Current vaccine -- (ENGERIX-B, RECOMBIVAX-HB) is a recombinant product derived from HBsAg expressed in yeast. Excellent protection has been shown in studies of men who have sex with men and in medical personnel

EPIDEMIOLOGY OF Hep C

Spread parenterally - use to cause post-transfusion hepatitis May be sexually transmitted but to a lower extent than HBV Needle sharing accounts for 40% of cases Mother-child transmision 150 million cases worldwide; 350,000 deaths from HCV-related liver disease annually Most pravalent in middle east, particularly Egypt In U.S. 3.2 million pple infected; 17000 new cases annually

Replication of Hep B

The partially dsDNA goes into nucleus partially incomplete strand (positive polarity unlike the complete strand) is formed into a circular dsDNA using RT Host RNA Pol transcribes the dsDNA to make the viral proteins Replicate thru an RNA intermediate and then to DNA which integrates into the genome

Epidemiology of HEP A

Transmitted by fecal-oral route Outbreaks of hepatitis A have been linked to the ingestion of undercooked seafood, usually shellfish from waters contaminated with human feces. Common-source outbreaks related to other foods, including vegetables as well as contaminated drinking water, have also been reported. High risk in sexually active gay men, illicit drug users and travelers from developed to developing countries The risk of clinically evident disease is much higher in infected adults than in children. Patients are most contagious in the 1 to 2 weeks before onset of clinical disease.

HEP B oncology

causes HCC PreS/S2 gene product appears to stimulate c-myc in trans

Hep D transmission

co-infects w/ Hep B percutaneous: Injecting drug use Permucosa: sex contact

Pathogenesis of HEP C

transmitted via blood to blood derived products Invades blood T and B lymphocytes and monocytes before moving to main site of infection --- Liver highly replicates in the liver CTLs damage infected hepatocytes Interaction of HCV core with tumor necrosis factor (TNF) receptor decreases cytolytic T-cell activity and interference of HCV nonstructural (NS3/NS4A/NS4B) proteins with interferon pathways HCV infection is inhibited by the release of interferon-γ, which recruits intrahepatic inflammatory cells, stimulates helper T1 (TH1) response, and induces *necrosis or apoptosis of HCV-infected cells* -- Th1 cell secrete TNF-alpha which triggers cytokine storm and cause liver damage and necrosis Adaptive immune responses, including cell-mediated and humoral responses are elicited after expression of HCV proteins, especially the envelope glycoproteins E1 and E2. HCV antibodies appear several weeks after infection, and because of selective pressure from the host, mutations take place in the E2/E1 proteins, allowing the virus to evade the humoral immune response and establish persistent infection.