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Flashcards in day 1 - viral hepatitis Deck (28):

what is hepatitis A and how is it transmitted

Hepatitis A virus (HAV) is a single stranded RNA virus with an incubation period of approximately 2 to 6 weeks. HAV has a world-wide distribution, but is especially common in the tropics.

HAV is transmitted via the faecal-oral route following faecal contamination of food and water. Raw or poorly cooked shellfish are often implicated. Epidemics occur. Sexual transmission may occur through oro-anal intercourse and there is an increased frequency of infection amongst homosexual men in the UK.

HAV is maintained in human populations by case to case transmission. HAV enters the body via GI tract. Primary multiplication probably occurs in the gut. The virus then spreads to the liver where it multiplies in the hepatocytes. Virus is present in the faeces for about two weeks before the onset of jaundice, but usually only for a few days after the onset of symptoms. HAV has recently been transmitted by high purity clotting factor concentrates.


clinical features of hepatitis A (HAV)

Prodromal symptoms consisting of malaise, anorexia, nausea; aversion to fatty foods and cigarettes may be present. The severity of the icteric phase of the illness is age related with adults more likely to suffer a symptomatic infection. The overall mortality is less than 0.1%. Most acute HAV infections resolve over a period of weeks. However, the hepatitis may relapse within a few weeks of apparent recovery. There is no carrier state.


diagnosis of HAV infection

This is made serologically by the detection of HAV-specific IgM or by demonstrating seroconversion for antibody.


treatment of HAV

This is conservative with complete resolution in most cases.


prophylaxis for HAV

HAV infection may be prevented by either passive immunisation with human normal immunoglobulin or active immunisation with HAV vaccine. This is a killed whole virus vaccine prepared from tissue cultured HAV.


what is HBV and how is it transmitted

Hepatitis B (HBV) is a double stranded DNA virus with an incubation period of 2 to 6 months. The virus itself, the Dane particle, has a distinctive morphology and was first visualised in this medical school. HBV may be transmitted sexually, from mother to child or by parenteral inoculation. Sexual transmission of HBV is common. HBV is usually maintained in populations by infectious carriers rather than by acute case to case transmission. It is common in the tropics. Blood and blood products, in spite of screening, may transmit infection. Hospital staff are at risk of infection through needlestick exposure, they may also pass HBV to their patients.

The site of early replication is not known but may be the Küpffer cell. HBV spreads through the liver and expression of HBcAg can be seen in hepatocyte nuclei with HBsAg and HBeAg in the cytoplasm. Virus and viral antigens are shed into the blood. HBV is not cytopathic and the liver damage is immune mediated.


clinical features of HBV

A prodrome of malaise, anorexia, arthralgia and arthritis may be present. The acute infection is often subclinical, particularly in children. The mortality associated with an acute infection is less than 1%. Approximately 5-10% of acutely infected adults will become HBV carriers. Acute infections which present with jaundice virtually never leads to chronic carriage. A history of jaundice in the remote past does not indicate a risk of HBV carriage. HBV infections in neonates and immunosuppressed patients are likely to persist. These patients are termed carriers and this carrier state may persist for life.

Carriers may develop chronic liver disease, cirrhosis and primary liver cell cancer. Some HBV carriers may also develop extra-hepatic disease, for example glomerulonephritis in children and polyarteritis nodosa. HBV carriers are classified as high infectivity and low infectivity carrier on the basis of their hepatitis B e antigen status (see below). Initially carriers are of high infectivity with their serum containing high levels of HBsAg, HBeAg and virions. Sometimes referred to as ‘supercarriers’ they represent the principal reservoir of infection. After time, the infection becomes partially suppressed. HBsAg remains in the serum but HBeAg is replaced by anti- HBe and virions virtually disappear from the circulation. Such carriers are far less infectious and are often referred to as ‘simple carriers’.


diagnosis of HBV

The diagnosis of a current or past HBV infection or immunisation with HBV vaccine is usually made serologically based on presence of various HBV antigens and antibodies to these.

acute infection - HBV surface antigen usually present, anti-HBV surface antigen is not. anti-HBc IgM present.

past infection/immunisation - HBV surface antigen not present, Antibody to hepatitis B surface antigen is.


treatment of HBV

Management of the acute infection is usually conservative.
Conventional interferon alpha, pegylated interferon alpha and nucleos(t)ide analogues such as lamivudine, adefovir, entecavir, telbivudine and tenofovir have been used in chronic carriers in attempts to switch the patient from being supercarriers (HBeAg) to simple carriers (anti-HBe).

Treatment may be monitored by using quantitative real-time PCR to measure the circulating ‘viral load’. The long- term effects, safety and tolerability of these drugs is uncertain and the development of drug resistance remains a significant problem.

The treatment of an acute HBV infection is
conservative with most patients being managed on an out-patient basis. The patient's liver function, coagulation profile (prothrombin time) and HBV status (HBsAg, HBeAg, anti-HBe and anti-HBs) should be monitored into convalescence. The patient should be advised not to drink alcohol and to avoid other potentially hepatotoxic drugs until the hepatitis has resolved.


prophylaxis for HBV

Prophylaxis is given either by passive immunisation with hyperimmune hepatitis B immunoglobulin (HBIG) and/or by active immunisation with hepatitis B vaccine. Originally made from human plasma, this is now produced as a recombinant protein in yeast. Care with handling blood and sharp instruments in hospitals will reduce exposure. Nowadays all staff (including medical students!) should be immunised.

Staff conducting exposure-prone procedures (EPPs), i.e. those most likely to lead to accidental inoculation, are now screened for infection if not found to be immune. HBeAg carriers will not be allowed to perform EPPs.


HCV features and transmission

Hepatitis C virus (HCV) is a single stranded RNA virus with an incubation period of 2- 3 months. Prior to the introduction of blood donor screening for antibody to HCV (anti-HCV) this was the most important cause of post-transfusion non-A, non-B hepatitis. HCV infection can also be acquired through needlestick injuries in health care workers or via shared needles among intravenous drug users.

Carriers represent the most significant reservoir of infection by which HCV is maintained in the population.
Transmission from mother to child has also been documented. HCV may occasionally be transmitted sexually.

Six different genotypes are described and the virus is genetically quite diverse.


HCV clinical features

Most acute infections will be subclinical. When symptoms present they are usually mild (lethargy and anorexia). Jaundice is uncommon, occurring in only about 10% of cases. The majority of acute infections (over 70%) will develop into chronic persistent infections.

Chronic HCV infection is associated with the development of chronic liver disease including chronic hepatitis, cirrhosis and primary liver cell cancer. A chronic HCV infection may also act as a trigger factor for the development of autoimmune liver disease, mixed essential cryoglobulinaemia and porphyria cutanea tarda.


HCV diagnosis

Serology. Seroconversion for antibody to HCV (anti-HCV) may be delayed for several months after an acute HCV infection. Serology is therefore useful to diagnose a chronic, but not an acute, HCV infection.

Detection of HCV RNA. HCV RNA can be detected in the serum of an HCV-infected patient following amplification of serum viral RNA by RT-PCR. Detection of HCV- RNA may be used to diagnose acute infections. HCV antigen detection assays have recently become available and are being evaluated.


treatment of HCV

Chronic hepatitis carries a significant morbidity. Early studies with interferon alone lead to eradication of infection in less than 25% of carriers. Combined interferon and ribavirin treatment is more effective resulting in viral eradication in approximately 40% of cases. The use of pegylated interferon in combination with ribavirin has further improved the efficacy of treatment (~50% viral eradication), although the response rate in patients infected with genotypes 1 and 4 remains disappointing.

Determination of IL28B polymorphisms may be useful to identify a patient’s likelihood of response to treatment with pegylated interferon alpha and ribavirin; however, the predictive value is relatively low. Several protease inhibitors have been shown to be effective in clinical trials and two of these (telaprevir and boceprevir) are about to be introduced in the UK. Inhibitors of the RNA-dependent RNA-polymerase NS5B, as well as compounds that directly inhibit HCV replication through interaction with host cell proteins (e.g. cyclophilin) are also being investigated in clinical trials.

HCV treatment may be monitored by using quantitative real-time RT-PCR to measure the circulating ‘viral load’.


HCV prophylaxis

At present there is no prophylaxis other than care to prevent exposure to infection. Experimental vaccines are under development but there is no vaccine currently available.


properties of hepatitis D virus

Hepatitis D virus (HDV) is a defective single stranded RNA virus that is dependent on the envelope protein of hepatitis B for its own replication.


transmission and clinical features of HDV

Transmission is usually parenteral, but may also occur sexually. Prophylaxis is achieved by preventing HBV infection. There are two patterns of infection:

Co-infection - HDV infection occurs simultaneously with an HBV infection. Co- infection typically exhibits a relatively benign self-limiting course.

Superinfection - either acute or chronic infection of an HBV carrier by HDV. Superinfection of chronic HBV carriers with HDV is frequently associated with fulminant hepatitis and an increased risk of progression to chronic infection, severe chronic active hepatitis and cirrhosis


HDV diagnosis

Active HDV infection was until recently diagnosed by the presence of anti-HDV IgM antibodies. It is now diagnosed by the detection of serum HDV RNA using real-time reverse-transcription PCR assay. Anti-HDV IgG persists even after the patient has cleared HDV infection.


HDV treatment

Chronic HDV infection is difficult to treat and although interferon therapy may change the course of the disease in some patients, low rates of sustained virological response and relapse post treatment are common. The role of new nucleos(t)ide analogues such as tenofovir and entecavir that are able to reduce hepatitis B surface antigen levels is currently being explored.


hepatitis E virus features and transmission

Hepatitis E virus (HEV) is a single stranded RNA virus.
It is transmitted via the faecal-oral route and is usually associated with large water- borne outbreaks. In general there is a low secondary attack rate among household contacts.

Clinically HEV infection is usually a self-limiting disease resembling HAV. Chronic liver disease has not been documented. HEV infection is associated with an extremely high mortality in pregnant women (20%).


clinical features of HEV

The features of disease are similar to hepatitis A.


HEV diagnosis

This is made serologically by demonstrating seroconversion for antibody to HEV (anti-HEV). IgM class assays are currently unreliable. The detection of HEV RNA by RT-PCR may sometimes be used to confirm infection.


HEV treatment

This is supportive with complete resolution in most cases.


HEV prophylaxis

There is currently no prophylaxis other than ensuring a clean water supply.


hepatitis G features

This agent is better called GBV-c after the putative human source. It is a flavivirus- like agent, similar to HCV but distinct from it. Persistent infections are common with a prevalence of up to 2% in the UK population. Infections appear to resolve spontaneously. Neither acute nor chronic infections appear to be related to hepatic disease.


indications for HBV immunisation

Indications for hepatitis B vaccine include:

a) Injecting drug users.
Patients with multiple sexual partners, particularly prostitutes (men and women), homosexual and bisexual men.
Close contacts (household and sexual) of HBV-infected persons.
Babies born to HBV-infected mothers.
b) Patients receiving multiple blood transfusions or blood products, for example, haemophiliacs.
Relatives responsible for the administration of blood products to, for example,
c) Health care and laboratory workers who have contact with blood or blood-contaminated body fluids.

Patients in chronic renal failure who will require double dose of vaccine. Staff and patients in residential accommodation for the mentally handicapped.

The vaccine used in this country is recombinant HBsAg, expressed in yeast cells which has been purified and adsorbed to an alum adjuvant.


progression of an untreated HCV infection

After acute infection, 15% to 40% of HCV-infected individuals appear to spontaneously clear the virus within approximately 6 months, thereby resolving their infection without sequel. Although their hepatitis C antibody test will remain positive and confirm the presence of prior infection, sensitive molecular tests will not show the presence of circulating HCV, and therefore, the patient is not at risk for developing hepatitis C–mediated liver disease or transmitting the disease to others.

However, 60% to 85% of exposed individuals will not clear the virus and therefore will remain chronically infected. The most important consequence of chronic HCV infection is progressive liver fibrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). Fortunately, only approximately 10% to 15% of patients with HCV infection progress to cirrhosis over a period of 20 years after infection.

One of the most serious complications of cirrhosis is the development of liver cancer (HCC) and liver failure. Hepatocellular carcinoma occurs almost exclusively in patients who have already progressed to cirrhosis. It has been estimated that up to 3% of people with cirrhosis develop HCC each year, and approximately 25% of patients with cirrhosis can be expected to develop HCC or liver failure. Thus, liver cancer and liver failure occur in approximately 2% to 4% of patients who are exposed to HCV over a 20- to 25-year period.


how do you assess the severity of liver disease in HCV infection?

The gold standard method for assessing liver disease severity in hepatitis C is the liver biopsy.

The liver biopsy provides useful information about the degree of inflammation and fibrosis in HCV-infected patients, which in turn predicts the need for HCV treatment, the future risk of cirrhosis, and the need for reinitiation of therapy after treatment failure.

Recognizing that the majority of HCV-infected patients will have limited liver damage, the liver biopsy is an invaluable tool for making treatment decisions, particularly in patients who may not be ideal treatment candidates but in whom treatment would be contemplated if it were needed. For instance, a patient with comorbid depression may be more challenging to treat for HCV because interferon may exacerbate depressive symptoms and suicides have been reported. Therefore, a decision to treat this patient’s hepatitis C must be carefully considered, and only the liver biopsy can accurately quantify the amount of liver damage.
Although the majority of liver biopsies will show limited liver damage and therefore allow a safe postponement of HCV therapy, those who have more advanced disease and who are in need of treatment will be accurately identified, even if they may have relative treatment contraindications.