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Lecture notes: Hepatitis

Acute hepatitis may occur as part of the clinical course of a number of viral infections, including Human Cytomegalovirus, Epstein-Barr virus, Herpes Simplex Virus, Yellow Fever Virus and Rubella. But the term "hepatitis virus" is usually used to describe infections caused by agents whose primary tissue tropism is the liver. To date, at least five hepatitis viruses have been recognised and these have been named, hepatitis A, B, C, D and E.

Clinical Features
Hepatitis due to all these viruses presents clinically in a very similar fashion, especially during the acute phase. Thus, a specific diagnosis can only be made in the laboratory. The majority of infections are often asymptomatic or produce only mild non-specific symptoms. But, common clinical features include: anorexia, nausea, vomiting, right upper quadrant pain and raised liver enzymes AST and ALT. Jaundice is the hall mark of infection, but tends to develop late. Anicteric cases are also very common.

ENTERICALLY TRANSMITTED HEPATITIS: A and E

Hepatitis A

Virology

Order: Picornavirales
Family: Picornaviridae
Genus: Hepatovirus
Species: Hepatitis A virus
Structure: small; 27 nm in diameter, non-enveloped spherical particle
Genome: +ssRNA (positive sense, single stranded RNA)


EM photo of Hepatitis A, courtesy of Prof Linda Stannard, UCT

Clinical Features

Incubation period 3-5 weeks (mean 28 days)
Incubation is followed by a pre-icteric phase lasting about 5 days.
The subsequent icteric phase resolved within 3 months in 85% of cases.
Convalescence may be prolonged, and fatigue and alcohol intolerance can last up to 18 months. There is no chronic form of the disease.
Milder disease than Hepatitis B; asymptomatic infections are very common, especially in children. Adults, especially pregnant women, may develop more severe disease. Complications:
Fulminant hepatitis: rare; 0.3-1.8 % of cases
Highest risk: pregnant women, elderly, pre-existing liver disease, other chronic medical conditions
Pathogenesis
Virus enters via the gut; replicates in the alimentary tract and spreads to infect the liver, where it multiplies in hepatocytes. Viraemia is transient. Virus is excreted in the stools for two weeks preceding the onset of symptoms.

Epidemiology

World-wide distribution; endemic in most countries. The incidence in first world countries is declining. There is an especially high incidence in developing countries and rural areas, where 80-90% of people are infected by the age of 5 years. The implication for South Africa is that most people, especially from rural areas, are seropositive, and donated blood/plasma contains sufficient levels of antibodies for use as passive immunity.

Transmission: Faecal-oral route

  1. Case-to-case; via faecal-oral route. Virus is excreted in stool in large amounts before the onset of symptoms. Outbreaks in creches are very common. In populations where oro-anal sex is prevalent, HAV is sexually transmitted via the faecal-oral route.
  2. Contamination of food or water with sewage

Infected food handlers
Shell fish grown in sewage-polluted water

Diagnosis

Virus cannot be cultured in vitro from clinical material; diagnosis depends on:
Serology HAV-specific IgM

Prevention

Active Immunization
Inactivated cell culture derived vaccine is available; it is recommended for travellers to third world countries and, indeed, all adults who are not immune. It is the recommended form of post-exposure prophylaxis if the exposure is identified early, and if there are no predisposing risk factors for severe disease. If there are such risk factors, or if prophylaxis is delayed, passive immunization in addition to vaccination is recommended.

Passive immunisation
Normal immunoglobulin (antibody prepared from pooled human serum) given to close contacts of acute cases.
Protection is short lived: three months

Hepatitis E

Virology

Order: none
Family: Hepeviridae
Genus: Hepevirus
Species: Hepatitis E virus
Structure: 27-34 nm in diameter, non-enveloped spherical particle
Genome: +ssRNA (positive sense, single stranded RNA)

Clinical Features

Incubation period: 45 days [2-9 weeks]
Acute, self limiting hepatitis
Most cases occur in young adults, 15-40 years

Complications

10 % develop fulminant hepatitis (more common in pregnant women). Mortality rate is high (20-40 %). Chronic hepatitis may develop in organ transplant patients and HIV-infected individuals and lead to cirrhosis.

Pathogenesis

Acute hepatitis E is similar to hepatitis A; virus replicates in the gut initially, before invading the liver and virus is shed in the stool prior to the onset of symptoms. Viraemia is transient. A large inoculum of virus is needed to establish infection. Chronic hepatitis E infection seems similar to chronic hepatitis C infections, but much about the pathogenesis is unknown.

Epidemiology

Prevalence of infection appears to be low in first world countries. Large outbreaks have been described in India, Mexico and North Africa where the source of infection is usually gross faecal contamination of drinking water supplies, which is the main source of infection.
Case-to-case transmission to household contacts appears to be uncommon. This suggests that a large inoculum is needed to establish infection.
Various animal species such as the domestic pig have been identified as reservoirs of the virus and outbreaks of human infections have been recorded associated with the consumption of inadequately cooked meat.

Outbreaks of hepatitis E have been confirmed in South Africa, but the prevalence of infection is unknown, as there are no routine laboratory tests yet available.

Diagnosis

No routine laboratory tests are available as yet in South Africa. Virus cannot be cultured in vitro.
1) Calicivirus-like particles in the stool, by electron microscopy
2) Specific IgM in serum (not yet available in South Africa)
3) PCR for HEV-specific sequences in stool or serum - currently research only

PARENTERALLY TRANSMITTED HEPATITIS B, C and D

Hepatitis B

Virology

Order: none
Family: Hepadnaviridae
Genus: Orthohepadnavirus
Species: Hepatitis B virus
Subtypes: A-H
Structure: 42 nm in diameter, enveloped spherical particle [also called the Dane particle]
Genome: circular DNA, incompletely double stranded; 3.2 kilobases in size
Excess surface antigen is produced, forming spheres and cylinders 22nm in diameter


EM photo of Hepatitis B, courtesy of Prof Linda Stannard, UCT

Clinical Features

Incubation period is long: 30-180 days, average 75 days
Insidious onset of symptoms. Tends to cause a more severe disease than Hepatitis A, but asymptomatic infections occur frequently, especially in the very young, who tend to develop immunotolerance and therefore a lesser immune response to the virus - this results in decreased inflammation in the liver as well as a higher rate of chronicity. Approximately 5% of adults develop a chronic infection, whereas 90% of infants infected vertically go on to chronicity.

Pathogenesis

Infection is parenterally transmitted. The virus replicates in the liver and virus particles, as well as excess viral surface protein, are shed in large amounts into the blood. Viraemia is prolonged and the blood of infected individuals is highly infectious. The host immune response to the virus is responsible for hepatocellular damage.

Complications

  • Persistant infection: Following acute infection, some individuals fail to eliminate the virus completely and become persistantly infected. The likelihood of this happening varies with age of exposure.
  • The virus persists in the hepatocytes and on going liver damage occurs because of the host's immune response against the infected liver cells.
  • Chronic infection may take one of two forms:
    • Chronic persistent hepatitis - the virus persists, but there is minimal liver damage
    • Chronic active hepatitis - there is aggressive destruction of liver tissue and rapid progression to cirrhosis or liver failure.
  • Patients who become persistently infected are also at risk of developing hepatocellular carcinoma (HCC).
  • Fulminant hepatitis
  • This is a complication of acute infection. Rare; accounts for 1% of infections.
  • Extrahepatic manifestations include serum sickness, glomerulonephritis, and polyarteritis nodosa, and are due to deposition of immune complexes.
  • Co-infection with HBV and HIV results in faster progression towards severe liver damage.

Epidemiology

Prevalence of disease in Africa
There are 400-500 million persistant carriers of Hepatitis B world wide, 50 million of whom are in Africa. Carriage rates vary markedly in different areas. In South Africa, infection is much commoner in rural communities than in the cities.

Hepatitis B is parenterally transmitted

  • Sexual intercourse Predominant mode of spread amongst adults
  • Close personal contact spread amongst children and in families, often called "horizontal" spread. This is the most common mode of transmission in areas of high HBV prevalence, where infection is acquired early in life. In South Africa, there is a high rate of infections in children in the three to nine year age group. Also accounts for transmission in mental institutions and children's homes.
  • Vertical transmission

    Perinatal transmission from a carrier mother to her baby
    Transplacental (rare)
    During delivery
    Post natal ?? breast feeding ?? close contact
    This is a major mode of transmission in South East Asia.

  • Blood

    Blood transfusions, serum products
    Sharing of needles, razors
    Tattooing, acupuncture
    Renal dialysis
    Organ donation
    Note: these are rare today due to advances in screening blood and organ donors, and sterile medical techniques.

Prevention

Active Immunization
Four types of vaccine are available
Serum derived - prepared from s Ag purified from the serum of HBV carriers
Recombinant sAg - made by genetic engineering in Saccharomyces cerevisiae, also known as Brewer's yeast
Third generation vaccines genetically engineered producing different size surface antigens - these vaccines are not available in South Africa
Combination vaccines - vaccines containing HBV vaccine in addition to vaccines against other organisms, e.g. Hepatitis A+B

All these vaccines are equally safe and effective. Three doses induce protective levels of antibodies in 95% of vaccine recipients.
Universal immunization of infants was introduced in April 1995. Infants receive three doses: at 6, 10 and 14 weeks. However, if their mother is known to be chronically infected, they receive doses at birth, 1 month, and 6 months if their birth weight is >2kg, and an additional dose at 2 months if their birth weight is <2kg.
In addition, vaccine should be administered to people at high risk of infection with HBV:

  • Health care workers
  • Sexual partners of chronic carriers
  • Infants of HBV carrier mothers
  • Post exposure prophylaxis

Passive Antibody
Both Hepatitis B immune globulin and vaccine should be administered to non immune individuals following single episode exposure to HBV-infected blood.

Treatment of Chronic Hepatitis B infection

Two classes of drugs are used to treat chronic HBV infection

1. Interferons
Interferon α2a
Pegylated interferon α2a
Interferon-α enhances the host immune response to HBV and improves immune control of the virus. Clearance of infection (and immunity) is the best outcome, but is achieved in only around 25% cases (after a six month course of treatment). Interferon is the best available treatment for chronic HBV, but side effects and expense limit its use.
2. Nucleoside reverse transcriptase inhibitors
These drugs interfere with viral replication, but cannot clear HBV infection. They need to be taken life long (as for HIV) to control infection..
Lamivudine (3TC, LAM)*
Tenofovir (TDF)*
Entecavir (ETV)
Adefovir (ADV)
Telbivudine (LdT)
Clevudine (CLV)
Emtracitabine (FTC)*†

Note: * also used to treat HIV
† not registered for use against HBV, but is similar to lamivudine

Viral antigens:

1) surface antigen (sAg) surface (envelope) protein of the dane particle
Secreted in excess into the blood as 22 nm spheres and tubules presence in serum indicates that virus replication is occurring in the liver

2) e antigen (eAg) secreted protein; shed in small amounts into blood
presence in serum indicates that a high level of viral replication is occurring in the liver. May be negative in carriers with mutations in the e antigen gene who nonetheless have high level viraemia.

3) core antigen (cAg) core protein
present in infected liver cells, not found in blood

Antibody response:

1) Surface antibody (sAb, antiHBs)) becomes detectable late in convalescence following resolution of infection, remains detectable for life; not found in chronic carriers; indicates immunity

2) e antibody (eAb, antiHBe) becomes detectable as viral replication falls
In a carrier, it indicates low infectivity

3) Core IgM rises early in infection
indicates recent infection

4) Core IgG Rises early
present for life in both chronic carriers as well as those who clear the infection
indicates exposure to HBV
Usually tested as total core antibodies, and implies IgG in the absence of IgM

HBV viral load:
HBV viral load measures level of HBV DNA in blood. This is the most reliable marker of infectivity. It is more reliable than e antigen which can be negative in some carriers due to mutations in the e antigen gene

Hepatitis B serology

(a) Acute, self limiting infection

(b) Chronic carrier state

 

Hepatitis C

The major cause of parenterally transmitted non A non B hepatitis. It eluded identification for many years because the virus could not be cultured. In 1989, the viral genome was cloned and sequenced from the serum of an infected chimpanzee. Much of the knowledge that we have today is based on analysis of its genome sequence

Virology

Order: none
Family: Flaviviridae
Genus: Hepacivirus
Species: Hepatitis C virus
Structure: 55-65 nm in diameter, enveloped
Genome: +ssRNA (positive sense, single stranded RNA)

Genome has a high mutation rate
Viruses do not grow in cell culture, and only infect humans and chimpanzees

Clinical Features

The incubation period is 15-150 days. Most common presenting symptoms are fatigue and jaundice, but 60-70% of cases are asymptomatic. It is the cause of 15-20 % of acute hepatitis in the developed world. Of note, 80% of newly infected individuals develop chronic infection..

Complications of chronic infection:

  • About 70% of those infected go on to develop a chronic infection.
  • Cirrhosis develops in 10-20% of chronic infections. Co-existence of other liver pathology increases the severity of HCV induced liver disease.
  • Hepatocellular carcinoma (HCC) develops in 1-5% of HCV-infected people, and HCV is responsible for about 25% of HCC cases.
  • Immune complex disorders common in HCV carriers
  • Co-infection with HIV is associated with more aggressive liver disease.
  • Extra-hepatic manifestations include unproven associations with cryoglobulinaemia, diabetes mellitus, and B-cell lymphoma..

Epidemiology

Approximately 170 million people are infected world wide. The prevalence is high in parts of Africa, the Eastern Mediterranean and South East Asia.

Transmission - similar to HBV

Intravenous drug abusers
Prior to the development of reliable labotatory tests for HCV, blood transfusions, blood products, organ donations were important transmission events
Community acquired: mechanism unclear
Vertical transmission and sexual intercourse play a minor role
Increased infectivity in patients co-infected with HIV.

Diagnosis

1) Serology
HCV-specific IgG - indicates exposure, not infectivity; Useful for detecting chronic infections, but is inadequate for detecting acute infection because it takes 2-3 months to become positive. .
2) PCR detects viral genome in patient's serum. The HCV genome is detectable in serum from 4-6 weeks post exposure (during acute infection). Indicates infectivity.

Treatment of Chronic infection: Interferon a in combination with Ribavirin results in clearance of infection in up to 40% of cases. Pegylated interferon a is interferon that has had polyethylene glycol attached to it. This increases the half life, which leads to fewer side effects due to a lower dose being used.

There is no vaccine available

Hepatitis D Virus (delta agent)

In 1977 an novel protein was discovered in the serum of some patients who were infected with Hepatitis B. It was named the delta antigen. Subsequent investigation showed that the protein was encoded by a new virus, now called the hepatitis D virus (HDV).
It is a defective virus which requires Hepatitis B as a helper virus in order to replicate. Infection therefore only occurs in patients who are already infected with Hepatitis B.

Clinial Features

Two forms of infection can occur - co-infection, where the person becomes infected with HDV and HBV at the same time, and superinfection, where the person becomes infected with HDV after the initial HBV infection. HDV leads to increased severity of liver disease in Hepatitis B carriers, and the acute infection has an incubation period of about 35 days. Fulminant hepatitis is ten times more common when a patient is co-infected with both viruses (HBV and HDV) simultaneously. With only HBV, 20-30% go on to develop cirrhosis, while that figure rises to 70-80% with co-infection and superinfection.

Virology

Order: none
Family: none
Genus: Deltavirus
Species: Hepatitis delta virus
Structure: 36 nm in diameter, encapsulated with sAg derived from HBV
Genome: circular -ssRNA (negative sense, single stranded RNA), 1700 nucleotides in length
The genome is the smallest genome of any virus known to infect humans.
Genome encodes only one protein, namely the delta antigen.

Epidemiology

First identified in intra-venous drug abusers in Italy. Has since been shown to be present in other parts of Europe as well as parts of North and South America. The incidence in South Africa is unknown.

Treatment and prevention
No specific treatment is available. HDV infection may be controlled by preventing HBV surface antigen production, but this may not always be possible even with complete suppression of HBV replication.
HDV infection can be prevented by preventing infection with HBV, for which there is a successful vaccine available.

 


 



 

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