Hepatitis B

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Introduction

Hepatitis B (Serum Hepatitis) is caused by the hepatitis B virus (HBV).

Hepatitis B is a blood-borne virus, which can be caught from blood or body fluids. The infectious dose is small, and the virus can persist outside the body, so that it can be caught from e.g. dried blood on sharps. It can also be acquired sexually.

Epidemiology and natural history of hepatitis B infection

(For a good summary of this, and of current management methods, see Miller's article.[1])

Worldwide, 300-400 million people have chronic hepatitis B (CHB) infection, and up to 40% of them will develop sequelae such as cirrhosis or hepatocellular carcinoma.

Hepatitis B is acquired from blood or body fluids, e.g. during sex. As the infectious dose is relatively small, and the virus can survive outside the body for considerable periods, it is important in medicine, as it can be transmitted via contaminated instruments or hands. It is also a hazard for unvaccinated medical staff, who are more likely to be infected by their patients, than to infect them.

The 'immune tolerant' phase of chronic hepatitis B infection

The virus has little direct harmful effect on the liver. The pathology is caused by the immune response to it. Many cases of hepatitis B are 'acquired vertically' - the infection transmitted mother to child. When the virus is acquired by an infant or foetus with an immature immune system there are two consequences:

  1. Most will become chronically infected - about 90%, as compared to about 5% of people infected as adults)
  2. The virus will replicated unchecked, and viral loads will be very high - typically greater than log108 IU, in the absence of significant liver damage, and therefore with normal liver function test results such as alanine transaminase (ALT).

The 'wild type' virus in these patients will carry the 'e' antigen. This is the 'immune tolerant' phase of chronic hepatitis B infection.

The 'immune active' phase of chronic hepatitis B infection

People infected as adults generally enter the 'immune active' or 'immune clearance' phase of chronic hepatitis B infection soon after infection; but people infected vertically can move into this phase at any time from teenage to the late 30s.

During this phase of infection the immune system comes to recognise the HBV as foreign, and mounts an immune response against it, including, at some point the production of anti-'e' antibodies ('HBe seroconversion'; 'anti-HBe').

In this phase the immune system can cause liver damage. It is usually asymptomatic, but there may be a short-lived rise in ALT levels. This phase usually lasts for at least 6 months, and may continue for several years. The longer it lasts, the more liver damage is sustained.

After this stage the virus may be cleared entirely, or the patient may become an 'inactive carrier'.

The 'inactive carrier' phase of chronic hepatitis B infection

In this phase - more correctly known as the 'low replicative phase' - viral infection persists, and can revert to significant levels. Patients can exit from this phase in the following ways:

  • The virus may be cleared by the immune system. This is usually accompanied by the development of antibodies to the virus' surface antigen (anti-HBs; 's' seroconversion) and the loss of this antigen (HBsAG) from their bloodstream and tissues.
  • The immune system may keep the virus in check but without clearing it. The patient remains a long-term, low-replicative carrier.
  • The immune system may feel to control the virus. The patient becomes e-antigen positive again, and re-enters the immune active phase, with further damage to the liver.
  • The virus may mutate, to evade immune control. Typically, this happens in older patients who have had long term chronic hepatitis B infection. Such mutant viruses typically have a characteristic genetic change, and no longer code for the 'e' antigen, causing e-negative chronic hepatitis B. Liver damage may be more severe than with non-mutated viruses.

Table relating to natural history of chronic hepatitis B infection

Chronic hepatitis B infection
Immune tolerant phase Immune active phase Inactive carrier phase e-negative hepatitis
ALT Normal Elevated Normal Fluctuating
HBV >20,000 IU Falling <2,000 IU >2,000 IU
'e' antigen/antibody HBe antigen positive Seroconverting HBe antigen negative
HBe antibody positive
HBe antigen negative
Liver histology Normal Inflammation and developing fibrosis Fibrosis depends on immune active phase Inflammation and developing fibrosis
Treatment recommended Nil Yes if prolonged or severe No Yes

Aetiology

Hepatitis B virus

Clinical

Acute hepatitis B infection is usually asymptomatic; in a minority it is prolonged, serious, and occasionally fatal.

Of those infected, 90% of infants infected at birth, 25-30% of 1-4 year olds, and 3-5% of individuals aged five years or more will proceed to chronic hepatitis B (CHB).

Some of those with CHB will be infectious, and some will develop cirrhosis, and/or hepatocellular carcinoma years or decades later. Each year in the UK there are 4500 acute hepatitis B infections, more than 7500 new cases of chronic infection with hepatitis B (mainly in immigrants), and up to 430 cases of hepatitis B related hepatocellular carcinoma are estimated to occur, with estimated NHS costs of £26m-£375m ($48m-686m; €37m-538m).

Outcome by Age of Infection
Age at infection Proportion who will develop chronic hepatitis B
Birth 90%
1-4 years 25-30%
5+ 3-5%

Worldwide, Hep B is a major cause of liver cancer, and thus a major carcinogen.

Acute or chronic hepatitis B - case definitions

Acute hepatitis B - case definition

HBsAg positive and anti-HBc IgM positive and abnormal liver function tests with a pattern consistent with acute viral hepatitis.[2]

(IgM may remain positive in chronic hepatitis B and therefore level of IgM may help determine whether case is acute or chronic. As different assays are used by different laboratories, the local consultant virologist should define whether IgM is low or high.)

Chronic hepatitis B - case definition

HBsAg positive twice at least 6 months apart

Or

HBsAg positive and anti-HBc IgM negative and anti-HBc positive.[3]

(IgM may remain positive in chronic hepatitis B and therefore level of IgM may help determine whether case is acute or chronic. As different assays are used by different laboratories, the local consultant virologist should define whether IgM is low or high.)

Investigations

Screening in primary care

Guidelines suggest patients who come from high prevalence countries or who have lifestyle factors (e.g. sex workers, iv drug users, multiple sex partners, gay men ) that put them at high risk of infection and/or symptoms that could be attributed to Hepatitis B should be offered testing. Screening for Hepatitis B should be considered in asymptomatic patients from high risk groups who are presenting in primary care for other reasons.

Blood tests

There are a number of markers of hepatitis B infection, including the presence or absence of viral antigens, and antibodies to these antigens, as well as markers of liver damage. The key antigens are the surface ('s'), core ('c') and 'e'-antigens (HBs, HBc, and HBe).

A consultation draft of a UK SMI (Standards for Microbiology Investigations was published on 12 June 2017.[4] It provides a useful explanation of the tests and their interpretation. (Once published, the final draft is likely to be available via the UK SMI website).

Interpretation of blood test results

Quick reference
Positive Result Interpretation
HBsAg Active Hepatitis B infection. Detectable during incubation period, acute hepatitis and chronic carrier state. Patient is considered infectious. Persistence beyond 6 months indicates chronic infection.
Anti-HBs Marker of recovery and immunity. Detectable 1-3 months after HBsAg disappears. In the absence of anti-HBc, indicates immunisation with HBV vaccine or passively acquired antibody via hepatitis B immune globulin.
Anti-HBc IgM Consistent with current or recent HBV infection. Antibody may persist 4-6 months after acute stage. Occasionally present in chronic active hepatitis. Routinely performed on HBsAg positive samples
Anti-HBc Detects both IgG and IgM. Indicates current or past HBV infection. May be present during the “window” period when HBsAg has disappeared, but anti-HBs is not yet detectable. May persist longer than anti-HBs and be the only marker for past HBV infection. Not associated with recovery or immunity.
HBeAg Suggestive of high degree of infectivity. Persistence beyond 10 weeks suggests chronic liver disease.
Anti-HBe Anti-HBe appears prior to loss of HBsAg and signals reduced level of infectious virus. Suggests early convalescence or past infection with HBV, but may also be seen in HBV chronic carrier state
Selected Hepatitis B Serology Interpretations
Interpretation HBsAg Anti-HBcIgM Hbe Ag Anti- HBe Anti-HBc Anti-HBs
No evidence of HBV infection neg neg neg neg neg neg
Acute HBV infection pos pos pos pos pos neg
Recent HBV infection – early convalescence neg pos neg pos neg
Previous HBV infection neg neg neg pos/neg pos pos
HBV vaccine response neg neg neg pos neg pos
Chronic HBV (if HBsAg pos for > 6 months) - low infectivity pos neg neg pos pos neg
Chronic HBV (if HBsAg pos for > 6 months) - intermediate infectivity pos neg neg neg pos neg
Chronic HBV (if HBsAg pos for > 6 months) - high infectivity pos neg pos neg pos neg

Radiology

Treatment

Medical

Treatment of chronic hepatitis B infection has recently been reviewed in the Lancet Infectious Disease.[5]

Therapeutic vaccines may be available in the future.[6]

Surgical

Surveillance and follow up of cases

Standards for surveillance and follow up of hepatitis B & C have been published by the Health Protection Agency.[7]

Prevention

Hepatitis B can be safely and effectively prevented by vaccination. The UK offers targeted vaccination for hepatitis B to people in particular risk groups, as described in the "Green Book" (S18.4). It has been argued that vaccination should be offered universally in the UK, as is WHO policy.[8]

Occupational health issues

Hepatitis B infection is a serious occupational hazard for healthcare workers. Infection and a carrier state also severely limits career options for doctors - they are obliged to avoid "exposure-prone" procedures. Healthcare workers are an obvious group for immunisation. Healthcare workers - particularly those practising "exposure prone procedures" - may also be a source of infection.

Vaccines required for occupational health reasons should be provided by the employer, not by the patient's GP (other than through a contractual relationship with the employer). [9][10][11][12][13][14] When the matter is clinical, then it is the GP's responsibility. Examples where vaccination is the GP's responsibility:[15]

  1. Completing the HepB immunisation schedule for a baby that had it started in hospital;
  2. The patient or household member of the patient identified by the GP as a drug addict (or other situation at which patient at risk other than due to travel or their occupation);
  3. A teacher in a a school with special needs children, bitten by one of the pupils and who has never been provided HepB vaccination by the employer (as long as this teacher attends his/her registered GP). As you can see, before the bite, it was the employer's responsibility, but once the problem is a clinical one (after the bite), the routine NHS services (e.g. GP, AED, WIC) take over.

Children placed with foster carers at short notice may have been exposed to hepatitis B infection and their hepatitis B status may not be known before placement. Guidance from DH therefore recommends that immunisation should be offered to these carers and their immediate families, as they may be at risk of infection.[16] Although money was provided to Health Authorities for this in 2002-3, and again in the following year, it is not at all clear whether this should be done through the global sum, or under the terms of a local enhanced service (LES).

Hepatitis B screening and immunisation for medical students

This section has been moved to Screening and vaccination before starting at medical school.

Medical school saints and sinners regarding occupational health screening of medical students

This section has been moved to here.

Post-exposure prophylaxis

See detailed guidance in Green Book.[17]

Children born to infected mothers

New guidance has been issued.[18] The following information has not been checked to ensure it is consistent with updated guidance.

At least 95% of children born to mothers infected develop chronic hepatitis B.

  • Babies born to infected mothers should be immunised with hepatitis B vaccine.
  • The baby should also receive hepatitis B immunoglobulin (HBIG) UNLESS
  • the mother is positive for anti-HBe, AND
  • the baby weighs ≥ 1500g.

These interventions should take place as soon as possible (within 24 hours of birth). Additional vaccinations should take place at 1, 2 and 12 months of age, and another dose with the routine pre-school booster jabs (usually at 4-5 years of age). Serology should be done to confirm response at 12 months. This vaccination schedule prevents infection in over 90% of cases. If the baby receives the first dose of vaccine at birth and completes the course, they can be breastfed (See British Liver Trust Document or hepatitis B chapter of the Green Book).

Table: Vaccination of term babies according to the hepatitis B status of the mother

Source: Green Book[19][20]

Vaccination of term babies according to the hepatitis B status of the mother
Hepatitis B status of mother Give hepatitis B vaccine? Give HBIG?
Mother is HBsAg positive and HBeAg positive Yes Yes
Mother is HBsAg positive, HBeAg negative, and anti-HBeAg negative Yes Yes
Mother is HBsAg positive where e-markers have not been determined Yes Yes
Mother had acute hepatitis B during pregnancy Yes Yes
Mother is HBsAg positive and anti-HBeAg positive Yes No
Mother is HBsAg seropositive and known to have an HBV DNA level equal to or above 1 x 106ius/ml in an antenatal sample (this criterion is from the updated guidance)[21] Yes Yes

Notification

All forms of viral hepatitis are notifiable diseases.

See also

Immunisation "Green Book" (hepatitis B chapter is chapter 18 of the August 2006 edition of the Green Book).

External links

References

  1. Miller A. Current management methods for hepatitis B. Viral hepatitis in practice 2010;2(1):1-4.
  2. Health Protection Agency. Standards for surveillance and follow up of hepatitis B & C. April 2006.
  3. Health Protection Agency. Standards for surveillance and follow up of hepatitis B & C. April 2006.
  4. Public Health England National Infection Service. UK Standards for Microbiology Investigations: Investigation of hepatitis B infection (consultation draft). London: National Infection Service, Public Health England, 2017 (June 12).
  5. Papatheodoridis GV, Manolakopoulos S, Dusheiko G, Archimandritis AJ. Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. The Lancet Infectious Diseases 2008;8(3):167-178 (via Science Direct - login required) - or abstract via Lancet ID site
  6. NanoBio Launches Development Program for a Therapeutic Intranasal Vaccine for the Treatment of Hepatitis B. 2010 (22 April) Fierce Biotech Report (last viewed 22 April 2010)
  7. Health Protection Agency. Standards for surveillance and follow up of hepatitis B & C. April 2006.
  8. English P. Should universal hepatitis B immunisation be introduced in the UK? Archives of Disease in Childhood 2006;91:286-289; doi:10.1136/adc.2005.080028 Also available online from BMJ (subscription required, last accessed 19th April 2006.)
  9. Wessex Local Medical Committees. Hepatitis B and Occupational Health: FAQs. October 2010 (Updated August 2012). Last viewed 2015 (8 April).
  10. General Practitioners Committee (BMA's 'GPC'). Hepatitis B immunisation for employees at risk: guidance for GPs. August 2005.
  11. BMA. Hepatitis B immunisation for employees at risk. 2005. Last updated November 2005. Last viewed 21 November, 2007. May require prior member log-in to BMA website.
  12. BMA. Focus on private practice. June 2004 (updated April 2005). Last viewed 9 February, 2007. May require prior member log-in to BMA website.
  13. Health & Safety Executive. Blood-borne viruses in the workplace: guidance for employers and employees. In: Executive HS, editor. London: HSE Books, 2001
  14. Advisory Committee on Dangerous Pathogens. Infection at work: Controlling the risks. A guide for employers and the self employed on identifying, assessing and controlling the risks of infection in the workplace. London: Advisory Committee on Dangerous Pathogens, 2003
  15. G Kassianos (RCGP vaccination spokesperson). Personal communication. 2006.
  16. Department of Health. Children in need and bloodborne viruses: HIV and hepatitis. London: Department of Health & Department for Education and Skills, 2004 (Gateway Ref: 3766)
  17. Salisbury D, Ramsay M, Noakes K, editors. Immunisation against infectious disease. 3rd Edition ed. London: HMSO, 2006 (pages 173-4 and table 18.5 on p176).
  18. Ramsay M. Policy on the use of passive immunisation with hepatitis B immunoglobulin (HBIG) for infants born to hepatitis B infected mothers. London: Health Protection Agency Centre for Infections, 2008 (12 August).
  19. Salisbury D, Ramsay M, Noakes K. Table 18.4: Vaccination of term babies according to the hepatitis B status of the mother. Immunisation against infectious disease. 3rd Edition ed. London: HMSO, 2006:173
  20. Ramsay M. Policy on the use of passive immunisation with hepatitis B immunoglobulin (HBIG) for infants born to hepatitis B infected mothers. London: Health Protection Agency Centre for Infections, 2008 (12 August).
  21. Ramsay M. Policy on the use of passive immunisation with hepatitis B immunoglobulin (HBIG) for infants born to hepatitis B infected mothers. London: Health Protection Agency Centre for Infections, 2008 (12 August).
  22. Davison SA, Strasser SI. Ordering and interpreting hepatitis B serology. BMJ 2014;348.Subscription or membership may be required.</small</li></ol>

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