GIT micro 7

I. INTRODUCTION

• Refers to inflammatory condition of the liver 

• Commonly caused by a viral infection but there are other possible causes of hepatitis

A. OTHER POSSIBLE CAUSES OF HEPATITIS

• Alcoholic hepatitis is caused by heavy alcohol use.

• Toxic hepatitis can be caused by certain poisons, chemicals, medicines, or supplements.

• Autoimmune hepatitis is a chronic type in which your body’s immune system attacks the Liver. The cause is not known but genetics and environment may play a role.

B. HEPATITIS VIRUS

• Many viruses cause hepatitis

• There are five clinically important viruses called hepatitis viruses because their main site of infection is the liver:

  • Hepatitis A

  • Hepatitis B

  • Hepatitis C

  • Hepatitis D

  • Hepatitis E

  • Hepatitis G (not included in the 5 but was presented in the slide)

• Other viruses such as the Epstein-Barr virus which is the cause of infectious mononucleosis, cytomegalovirus, and yellow fever virus infect the liver but also infect other sites in the body. 

  • Therefore, they are not exclusively hepatitis viruses. 

• Hepatitis viruses discussed in this lecture come from different viral families. 

  • Some are DNA viruses, RNA viruses, enveloped and non-enveloped. 

  • They are united by their ability to infect the hepatocytes because they have proteins on their surface that react with the receptors on the surface of hepatocytes. 

  • They are non-cytotoxic that they do not kill hepatocytes directly. 

  • The death of hepatocytes is mediated by cytotoxic T-cells directed against viral antigens displayed on the surface of the hepatocytes in association with MHC Class I proteins.

II. HEPATITIS A

• Hepatitis A virus causes HEPATITIS A.

• It is classified as a member of the Hepatovirus Genus within the Family Picornaviridae.

• Hepatovirus with a non-enveloped, single-stranded RNA

  • Replicated in the cytoplasm

• Has only one serotype

  • NO antigenic relationship to Hepatitis B virus or other hepatitis viruses

• Destroyed by boiling within 5 minutes

• Resistant to organic solvents and detergents and can survive in acidic environments to a pH of 3

• Inactivated by hypochlorite/bleach and quaternary ammonium formulations containing HCl, which are found in many toilet cleaners

• Major natural hosts: humans (ONLY important reservoirs)

A. EPIDEMIOLOGY 

1. OUTBREAKS

• Outbreaks occur in special living situations such as:

  • Summer camps

  • Boarding schools

  • Among the homeless

• Diseases:

  • Common in crowded areas

  • Mental hospitals

  • Schools for the retarded

  • Daycare centers

• Common sources of outbreaks arise from fecally contaminated water or food such as oysters grown in polluted water and eaten raw or ingestion of undercooked seafood

  • Infectivity remains from days to months in live oysters, wastewater, fresh waters, sea waters, soils or marine sediment.

2. MODES OF TRANSMISSION 

• Person-to-person via oral fecal route

  • Transmission is fecal oral with peak viral shedding before onset of symptoms.

  • Virus appears in the feces roughly 2 weeks before the appearance of symptoms, so quarantine of patients is ineffective.

• Intimate contact (anal intercourse)

  • Spread is most common in person-to-person, including sexual contact and in men who have sex with men

• Food borne and waterborne

  • It can occur as food-borne and waterborne transmission with consumption of raw and partially cooked shellfish and among food handlers.

• Most common risk factors in the US:

  • International travel and close contact

  • Sexual or household with the Hepatitis A infected person

B. PATHOGENESIS

• Virus replicates initially in the enteric mucosa followed by a period of viremia with spread to the liver.

  • The pathogenesis of Hepatitis A viral infection is not completely understood.

  • The virus probably replicates in the GIT and spreads to the liver via blood.

  • Hepatocytes are infected, but the mechanism by which cell damage occurs is unclear. 

  • It is likely that attack by Cytotoxic T cells causes damage to the hepatocytes.

• Not associated with chronic carrier state

• Self-limiting infections in 99% of cases

  • The infection is cleared, the damage is repaired, and no chronic infection ensues. Almost everyone recovers fully from Hepatitis A with a lifelong immunity.

C. MANIFESTATIONS

• Hepatitis A is a viral liver disease that can cause MILD to SEVERE illness

  • The clinical manifestations of ACUTE HEPATITIS are virtually the same regardless of which Hepatitis virus is the cause.

• Incubation period: 10-15 days or 3-4 weeks (mean of 25 days)

  • Short Incubation Hepatitis compared to Hepatitis B which has 10-12 weeks incubation.

• Clinical Symptoms: fever, anorexia, nausea, vomiting, RUQ pain, and jaundice are typical

  • Onset of dark urine and clay-colored stools (pale feces) appear 1-5 days before the onset of jaundice

  • Most infections in children are asymptomatic and are detected by the presence of IgG antibody

  • Infections in adults are often symptomatic

• Elevated transaminases

• Recovery: days to weeks

  • Most cases resolve spontaneously in 2-4 weeks

• 10-15% of patients may experience relapse over 6 months after the acute illness.

  • Anicteric hepatitis: asymptomatic or mildly ill, absence of jaundice, with positive serologic evidence of infection.

• Infection-to-disease ratio:

  • Children - 20:1

  • Adults - 4:1

• NO chronic hepatitis or chronic state occurs

• NO predisposition to hepatocellular carcinoma.

D. DIAGNOSIS

• Hepatitis A virus infection is generally diagnosed by detecting

  • IgM antibodies through the virus; or

  • IgM anti-hepatitis A virus in the blood at the onset of symptoms

  • IgM specific antibody: ACUTE INFECTION

• Laboratory diagnosis is made by the detection of IgM antibodies to the Hepatitis A virus in a single acute-phase serum sample 

  • Detection of IgM antibodies is the most important test

  • Peak: 4 to 6 weeks after exposure

  • Persists for 3 to 12 months

• IgG anti-hepatitis A virus antibodies can also be used (DURING CONVALESCENCE)

  • Can be detected 1 week after IgM response

  • Have neutralizing activity and can persist for life

  • When present without IgM anti-hepatitis A virus: represents past Hepatitis A virus infection, i.e., an individual is protected against recurrent infection.

  • May also be detected for 2 to 6 months after immunoglobulin

• Hepatitis A virus can also be detected in stool/fecal specimens via electron microscopy.

• Isolation of virus in cell cultures is not a practical technique.

E. TREATMENT

• No specific treatment

  • No antiviral therapy is indicated for acute Hepatitis A.

• Recovery from symptoms following infection may be slow and take several weeks or months.

• Most illnesses are self-limited

  • Can be managed with supportive and symptomatic measures such as adequate nutrition and rest

F. PREVENTION

• Handwashing

• Heating food appropriately

• Avoiding consumption of contaminated food and water especially in Hepatitis A virus endemic areas (to reduce risk)

• Chlorination and certain disinfecting solutions (e.g., household bleach) in a 1 to 100% dilution are also effective in inactivating the virus.

• Improved sanitation, food safety, and immunization are the most effective ways to combat Hepatitis A.

• Safe and effective vaccines have been developed to prevent Hepatitis A virus infection.

1. PASSIVE IMMUNIZATION: IMMUNE SERUM GLOBULIN

• Administration of human serum immunoglobulin is an effective means of protecting individuals against Hepatitis A virus infection and disease.

  • If given before exposure, immunoglobulin will prevent infection with Hepatitis A virus.

  • If given during the incubation period, the severity of infection may be reduced and potentially clinical infections may be converted into sub-clinical.

• Protective if given before or during the incubation period

• Given to:

  • Household contacts

  • Eating of uncooked foods prepared or handled by an infected individual

  • Travel from low endemic areas to areas with high infection rates: before departure and at 3-4 month intervals and as long as heavy exposure continues

2. ACTIVE IMMUNIZATION

• Live attenuated vaccines have poor immunogenicity and have not been effective when given orally

• Inactivated virus vaccines which are formalin killed vaccines induce antibody titers similar to wild virus infections

  • Almost 100% protective

• Given for those with prolonged or repeated exposure to Hepatitis A

  • Inactivated virus vaccine given as a series of two intramuscular doses with the second dose (initial dose followed by a booster) given 6 to 12 months after the first. No subsequent booster dose is recommended.

    • For travelers to developing countries

    • For children 2 to 18 years

    • For men who have sex with men

3. PASSIVE-ACTIVE IMMUNIZATION

• If an unimmunized individual traveled to an endemic area within 4 weeks, then passive immunization should be given to provide immediate protection and the vaccine given to provide long term protection.

III. HEPATITIS B

• Liver infection caused by Hepatitis B virus

  • Cause Hepatitis B

  • Belongs to the family Hepadnaviridae

• Enveloped DNA virus

  • Envelope contains a protein called a surface antigen (Hepatitis B surface antigen), which is important for laboratory diagnosis and immunization

• Complete virion

  • 42 nm, spherical particle consisting of an envelope which contains the HBsAg (hepatitis B surface antigen), which is important for laboratory diagnosis and immunization. 

  • Has an icosahedral nucleocapsid core containing a partially double stranded circular DNA genome (double stranded with a short single stranded piece)

• Core which comprises the following

• The genome contains four genes, which are actually four open reading frames that encode five proteins

A. EPIDEMIOLOGY

• Found worldwide but is particularly prevalent in Asia

  • Globally more than 300 million people are chronically infected with Hepatitis B and about 75% are Asians

• Main reservoir of infection: chronic carriers

  • There is strong association between chronic infection and hepatocellular carcinoma, or also called hepatoma or HCC, which is an indication that Hepatitis B virus is a human tumor virus

1. MODES OF TRANSMISSION

• Direct contact with blood or bodily fluids

• Sexually transmitted through semen and vaginal fluids

• Vertical transmission (from mother to child)

• Occurrence of transplacental transmission is rare

• Blood transfusion

  • Blood screening with the presence of Hepatitis B surface antigen has greatly decrease transfusion associated causes of Hepatitis B

• Use of inadequately sterilized hypodermic needles or instrument

  • Needle-stick injuries exemplify only a small amount of blood is necessary; infection is especially prevalent in addicts who use intravenous drugs

B. PATHOGENESIS

• Host response-dependent on cellular immunity: patients with depressed T-lymphocyte function have a high frequency of chronic infection

• Chronic infection leads to progressive fibrosis and cirrhosis.

• About 5% of adult patients with hepatitis B virus infections become chronic carriers. 

• In contrast, 90% of infected newborns become chronic carriers. 

• Chronic carriage is most likely to occur when infection occurs in the newborn than in an adult. 

• Probably because a newborn’s immune system is less competent than that of an adult. 

• Chronic carriage resulting from neonatal infection is associated with a high risk of hepatocellular carcinoma. 

• A chronic carrier is someone who has hepatitis B surface antigen persisting in their blood for 6 months or longer. 

• Chronic carrier state is attributed to a persistent infection of the hepatocytes resulting in a prolonged presence of hepatitis B virus and hepatitis B surface antigen in the blood.

• The main determinant of whether a person cures the infection or becomes a chronic carrier is the adequacy of cytotoxic T cell response.

• Lifelong immunity occurs after natural infection and is mediated by antibodies against the Hepatitis B surface antigen (HBsAb). 

C. MANIFESTATIONS

• Many hepatitis B infections are asymptomatic and are detected only by the presence of antibodies through the hepatitis B surface antigen. 

• The mean incubation period for hepatitis B is 10-12 weeks which is much longer than that of hepatitis A.

• The clinical appearance of acute hepatitis B is similar to that of Hepatitis A. 

• Symptoms of Hepatitis B tend to be more severe and prolonged than Hepatitis A, and life-threatening hepatitis can occur

• Most chronic carriers are asymptomatic, but some have chronic active hepatitis that can lead to cirrhosis and death

D. DIAGNOSIS

• Acute episode of disease

• Large amounts of HBsAg, HBV DNA, DNA polymerase, HBeAg, HBcAg

• HBeAg - arises during the incubation period and is present during the prodrome and early acute disease, and in certain chronic carriers (indicates a high likelihood of transmissibility)

• HBsAg and anti-HBc IgM appear in the serum early in the disease

• Anti-HBs

• Associated with the elimination of infection and protection against reinfection

• Persists for life in most individuals and provides long term immunity

• A positive (+) or active anti-HBs indicates that the person is protected against HBV, which may be a result of Hepatitis B vaccine or a successful recovery from a past Hepatitis B infection

• Past infection

• Presence of IgG and anti-HBc, anti-HBs or both

E. TREATMENT

• No antiviral therapy is typically used in acute Hepatitis B

• For people with mild symptoms, rest, adequate nutrition,and fluids are recommended.

• Those with more severe symptoms may need to be hospitalized.

• No role for steroids

F. PREVENTION

• The two main modes of prevention involve the use of either the hyper immune globulin or vaccine or both

• Post exposure treatment with Hepatitis B immune globulin (HBIG) reduces the development of symptomatic disease but this should be followed by active immunization with vaccine

• The subunit vaccine contains Hepatitis B surface antigen produced in yeasts by recombinant DNA techniques. The vaccine is highly effective in preventing hepatitis B and has few side effects. The cell conversion rate is approximately 95% in healthy adults

• Combination of passive and active immunization

• In passive and active immunization both immediate protection and long term protection are provided.

• Both the vaccine and human immune globulin should also be given to a newborn whose mother is HBsAg positive.

• This significantly reduces vertical transmission or the prevention of neonatal acquisition and development of chronic carriage in the neonate

• This passive and active immunization can also be used to provide immediate passive protection to individuals known to be exposed to HBsAg positive positive blood after an accidental needlestick injury.

• Safe sex practices

• Avoidance of needlestick injuries

• Avoidance of injection drug use

IV. HEPATITIS C

• The RNA virus which causes Hepatitis C is a member of the Flavivirus family

• More than 50%of the Hepatitis C infections result in chronic infection, a rate much higher than that of Hepatitis B

• Chronic Hepatitis C virus infection predisposes to hepatocellular carcinoma

• Humans: reservoir HCV/Hepatitis C Virus

• Transmitted primarily via blood

• At present, chronic injection drug use accounts for almost all new HCV infections.

• Transmission from mother to child during birth is another important mode of transmission.

• Transfusion of infected blood

  • Rarely occurs because donated blood containing antibodies to HCV is discarded.

• Transmission via needle stick injury occurs but the risk is lower than that of Hepatitis B virus.

• Sexual

  • Uncommon

• No evidence for transmission across the placenta or during breastfeeding.

• Needle sharing: 40%

  • People who share needles when taking IV drugs are very commonly infected.

A. MANIFESTATIONS

• Incubation period: average 6-12 weeks

• Infections are usually asymptomatic or mild or anicteric and detected only in the presence of antibodies.

• If symptoms such as malaise, nausea, and RUQ pain occur, they are milder than infection by the other hepatitis viruses.

• Fever, anorexia, nausea, vomiting and jaundice are common.

• Dark urine, pale feces, and elevated transaminase levels are seen.

• Note: Results in a chronic carrier state in up to 85% of patients (more often than with Hepatitis B) !

• Average time from infection to the development of chronic hepatitis is 10-18 years.

• Late sequelae of chronic hepatitis: cirrhosis and hepatocellular carcinoma (resembles Hepatitis B).

• Cirrhosis resulting from chronic Hepatitis C infection is the most common indication for liver transplantation.

B. DIAGNOSIS

• Antibody responses are usually delayed.

• They remained negative for 1-3 weeks in acute disease and may never become positive in 20% of patients with acute resolving disease.

• Serodiagnosis is difficult even with newer assays IgG antibodies may not develop for up to 4 months.

• Hepatitis C virus infection is diagnosed by detecting antibodies to the hepatitis C virus in an enzyme-linked immunoassay.

• If the result of the ELISA antibody test is positive, a PCR based test, that detects the presence of viral RNA or viral load in the serum, should be performed to determine whether active disease exists.

1. CURRENT TESTS

• Measure antibodies to multiple hepatitis C antigens for detection and quantification of hepatitis C RNA.

C. TREATMENT

• Current treatment of choice: a combination of drugs from three classes. 

• There are no vaccines

• Hyperimmune globulins are not available

• Pooled immune serum globulins are not useful for post exposure prophylaxis 

  • There is no effective regimen for prophylaxis following needlestick injury

  • Only monitoring is recommended

D. PREVENTION

• Avoidance of injection drug use

• Screening of blood products 

V. HEPATITIS D 

• Also known as Delta Hepatitis

• Caused by the hepatitis D virus 

  • Unusual virus because it is a defective virus that cannot replicate by itself because it does not have the genes for it envelope protein

• Found only in persons with acute or chronic hepatitis B infection 

  • Hepatitis B virus is the helper virus of hepatitis D virus because hepatitis D virus can only replicate in cells also infected by hepatitis B virus

  • Hepatitis D virus uses the surface antigens of hepatitis B virus called HBsAg as its envelope protein

• Protein-RNA complex is surrounded by HBsAg 

  • Virus uses HBsAg for assembling its coat

• Has one serotype

  • Because hepatitis B surface antigens has only one serotype

• No animal reservoir  

A. EPIDEMIOLOGY

• Hepatitis D virus is transmitted by the same means as hepatitis B virus:

  • Sexually

  • Blood

  • Perinatally

• In the United States, the incidence of Hepatitis D virus infections is low

  • most infections occur in intravenous drug users who share needles

• Worldwide, hepatitis D virus infections occur with a similar distribution to that of hepatitis B virus infections

  • Hepatitis D virus can only replicate in cells also infected by hepatitis B virus

  • Hepatitis D can only occur in a person infected with hepatitis B virus

• Most prevalent in groups in high risk of Hepatitis B

  • Injection drug users

  • Dialysis patients

  • Nonparenteral transmission

  • Vertical transmission

B. MANIFESTATIONS

• There are 2 major types of infection:

  • simultaneous delta and hepatitis B 

  • delta superinfection with chronic hepatitis B

C. DIAGNOSIS

• Diagnosis of Hepatitis D in the laboratory is made by detecting either Delta antigen or IgM antibody to the delta antigen in the patient’s serum.

• Tests for hepatitis D virus RNA in the blood is also available

D. TREATMENT

• There is no specific antiviral therapy For Hepatitis D virus

E. PREVENTION

• There is NO vaccine against Hepatitis D Virus

• Vaccination against Hepatitis B

  • Will not be infected by Hepatitis D Virus since Hepatitis D virus will not replicate if there is no infection from the Hepatitis B Virus

• Blood screening

  • Infected individuals should not donate organ, tissues, blood, or semen

• Safe sex

• Decrease use of contaminated needles and syringes by injection drug users

• Use of needle safety devices by workers

VI. HEPATITIS  E

A. EPIDEMIOLOGY 

• Non-enveloped, ssRNA virus (similar to but distinct from the Caliciviruses)

  • Thought to be more common than Hepatitis A in many developing countries

  • It is a common cause of waterborne epidemics of hepatitis in Asia, Africa, India, and Mexico, but uncommon in the US

  • Developing countries: Associated with Poor Sanitation

• Genus Hepevirus

• Has only 1 serotype

B. TRANSMISSION

• Fecal-Oral Route (Resembles Hepatitis A)

• Usually associated with Contaminated Drinking Water

C. MANIFESTATIONS

• Incubation Period: Approximately 5- days

• Infection is frequently subclinical (Like Hepatitis A)

  • Clinically, the Hepatitis E resembles Hepatitis A with an exception of high mortality rate in pregnant women

  • Most cases result without sequelae

D. DIAGNOSIS

• Confirmed by demonstrating the presence of specific IgM antibodies

• Typically made by detecting IgM antibodies to Hepatitis E Virus

•  Polymerase Chain Reaction (PCR)

  • Assay that detects Hepatitis E Virus RNA in patient’s specimen is available Clinically resembles Hep A with exception

E. TREATMENT AND PREVENTION

• No  antiviral drug is available for acute infection in immunocompetent patients

• Immune serum globulin: Protection likely but unproven

• Liver transplant: Only recourse in seriously ill patients

  • In immunocompromised patients, regathering cleared Hepatitis E Virus viremia in solid organ transplant recipients

• No vaccine

VII. HEPATITIS G

• In 1996, Hepatitis G Virus or HGV was isolated from patients with post-transfusion hepatitis

• RNA virus similar to Hepatitis C and members of the Flavivirus family

  • Hepatitis G Virus is a member of the Flavivirus   just like Hepatitis C Virus 

  • However, unlike Hepatitis C Virus, which is clearly the cause of both acute hepatitis and chronic active hepatitis and predisposes to hepatocellular carcinoma, Hepatitis G has not been documented to cause any of these clinical findings

  • The role of Hepatitis G virus in the causation of liver disease has yet to be established, but it can cause chronic infections lasting for decades.

  • Approximately 60%–70% of those infected clear the virus and develop antibodies

• Now classified as Hepatitis GB virus C (There is very little evidence that this causes hepatitis because it does not appear to replicate in the liver)

A. EPIDEMIOLOGY 

• It is carried in the blood of billions of people worldwide

• In the United States, it is found in the blood of approximately:

  • 2% random blood donors

  • 15% infected with Hepatitis C virus

  • 35% infected with HIV 

• Patients coinfected with HIV and Hepatitis G Virus have a lower mortality rate and have less HIV in the blood than those infected with HIV alone 

1. MODE OF TRANSMISSION

• Blood-borne 

• Sexual intercourse

2. CLOSE RELATIONSHIP WITH HEPATITIS C

• The majority of patients infected by hepatitis C are also infected by hepatitis G 

• Patients with both viruses do not appear to have worse disease than those with hepatitis C only 

B. DIAGNOSIS 

C. TREATMENT 

• None established