Presentation serological markers Laboratory test vaccinations Chronic hepatitis B Approach Harrison Davidsons Step up medicine Mksap Notes & notes Gastrointestinal disease Hepatology Risk group Management Hepatitis in pregnancy

1. Hepatitis B Virus
HBV
By Abo-alhassn haider

2. 01 INTRODUCTION AND EPIDEMIOLOGY
Hepatitis B is a double-stranded DNA hepadnavirus.
Globally, hepatitis A, B, C, D, and E are major public
health problems. About two billion people are
infected with hepatitis B.
cancer and cirrhosis resulting from these infections
account for about 3% of deaths worldwide.
Hepatitis B is one of the most common causes of
chronic liver disease and hepatocellular carcinoma
worldwide.
Approximately one-third of the world’s population
have serological evidence of past or current infection
with hepatitis B and approximately 350–400 million
people are chronic HBsAg carriers.

3. 01 INTRODUCTION AND EPIDEMIOLOGY
Acute, or fulminant, liver failure is uncommon and hepatitis B being the
most common infectious cause.
- Spread through
A. vertical transmission from mother to child (Perinatal transmission
is the most common route of hepatitis B infection worldwide.)
B. exposure to infected blood or body fluids( Sexual transmission
comprises 30% of hepatitis B infections in developed countries).

4. Prevalence of HBV infection varies greatly in different parts of the world. The
World Health Organization (WHO) has classified HBV prevalence into high (>8%),
intermediate (2- 7%) and low endemic <2 % areas In the WHO Eastern
Mediterranean Region, the WHO South-East Asia Region and the WHO European
Region, an estimated 3.3%, 2.0% and 1.6%% of the general population is infected.

5. 02 VIRUS PARTICLES
The hepatitis B virus consists of a core
containing DNA and a DNA polymerase
enzyme needed for virus replication.
The core of the virus is surrounded by
surface protein .The virus, also called a
Dane particle, and an excess of its
surface protein (known as hepatitis B
surface antigen) circulate in the blood.
Humans are the only source of
infection.
The hepatitis B virus can survive
outside the body for at least 7 days.
During this time, the virus can still
cause infection if it enters the body of a
person who is not protected by the
vaccine.

6. 03 SEROLOGICAL MARKERS
I. Hepatitis B surface antigen and antibody HBsAg
II. Hepatitis B core antigen and antibody HBcAg
III. Hepatitis B e antigen and antibody HBeAg
IV. Serum HBV DNA assays

8. I HBsAg
Hepatitis B surface antigen (HBsAg) is
the serologic hallmark of HBV infection
Presence of HBsAg in serum may
indicate acute
HBV infection, chronic HBV infection,
or asymptomatic carrier state.
In acute infection.
HBsAg persists in patients with
chronic hepatitis.

9. I HBsAg
HBsAg appears in serum 1 to 10 weeks after an acute
exposure to HBV, prior to the onset of hepatitic symptoms
or elevation of serum alanine aminotransferase (ALT).
HBsAg usually disappears within 1 to 2 months after
onset of symptoms
In patients who subsequently recover, HBsAg usually
becomes undetectable after four to six months.
Persistence of HBsAg for more than six months implies
chronic infection. It is estimated that less than 5 percent
of immunocompetent adult patients with genuine acute
hepatitis B progress to chronic infection

10. I HBsAg
The disappearance of HBsAg is followed by the appearance of hepatitis B
surface antibody (anti-HBs). In most patients, anti-HBs persists for life,
thereby conferring long-term immunity. In some patients, however, anti-
HBs may not be detectable until after a window period of several weeks to
months, during which neither HBsAg nor anti-HBs can be detected
At this time, the serologic diagnosis may be made by the detection of IgM
antibodies against hepatitis B core antigen (IgM anti-HBc)
The titer of HBsAg bears little relation to the severity of clinical disease.
These observations suggest that in hepatitis B the degree of liver cell
damage and the clinical course are related to variations in the patient’s
immune response to HBV rather than to the amount of circulating HBsAg.

11. II HBcAg
Hepatitis B core antigen (HBcAg) is an
intracellular antigen that is expressed in
infected hepatocytes. It is not detectable
in serum. Anti-HBc can be detected
throughout the course of HBV infection.
During acute infection, anti-HBc is
predominantly of IgM class.
IgM anti-HBc is the sole marker of HBV
infection during the window period
between the disappearance of HBsAg and
the appearance of anti-HBs.

12. II HBcAg
IgG anti-HBc persists along with anti-HBs in patients who recover from
acute hepatitis B. It also persists in association with HBsAg in those who
progress to chronic HBV infection
Isolated detection of anti-HBc can occur in three settings:
A. During the window period of acute hepatitis B when the anti-HBc is
predominantly IgM class
B. Many years after recovery from acute hepatitis B when anti-HBs has
fallen to undetectable levels
C. After many years of chronic HBV infection when the HBsAg titer has
decreased below the cutoff level for detection.
testing for IgM anti-HBc may be useful to distinguish between acute or
recent infection (IgM anti-HBc-positive) and chronic HBV infection (IgM anti-
HBc-negative, IgG anti-HBc-positive)

13. III HBeAg
Hepatitis B e antigen (HBeAg) is a
secretory protein that is processed from
the precore protein.
It is generally considered to be a marker
of HBV replication and infectivity.
The presence of HBeAg is usually
associated with high levels of HBV DNA in
serum and higher rates of transmission of
HBV infection from carrier mothers to
their babies and from patients to health
care workers.
Because HBeAg is invariably present
during early acute hepatitis B, HBeAg
testing is indicated primarily in chronic
infection

14. III HBeAg
HBeAg develops one week after HBsAg is detectable, but before symptoms
appear.
HBeAg to anti-HBe seroconversion occurs prior to HBsAg to anti-HBs
seroconversion HBeAg usually disappears about 3 weeks before HBsAg
disappears.
However, HBeAg seroconversion may be delayed for years to decades in
patients with chronic HBV infection.
Persistence of HBeAg beyond 12 weeks usually indicates progression to a
chronic carrier state.
HBeAg is a marker of infectivity in all patients except those who have
Hepatitis B virus (HBV) pre-core mutant or the core promoter mutant,
because they do not synthesise HbeAg, this is most commonly due to a
stop-codon mutation at nucleotide 1896.

15. IV HBV DNA
Like HBeAg, serum HBV DNA is an
indicator of HBV replication, but tests
for HBV DNA are more sensitive and
quantitative.
the PCR-based assay, which can
detect as few as 10 or 100 virions/mL.
These markers are useful in following
the course of HBV replication in
patients with chronic hepatitis B
receiving antiviral chemotherapy.

16. IV HBV DNA
in immunocompetent adults with chronic hepatitis B, a general correlation
exists between the level of HBV replication, as reflected by the level of
serum HBV DNA, and the degree of liver injury.
patients with chronic hepatitis B, high levels of HBV DNA increase the risk
of cirrhosis, hepatic decompensation, and hepatocellular carcinoma
IgM anti-HBc jointing HBV-DNA is most effective and most practicable in
distinguishing Acute Hepatitis B from Chronic Hepatitis B With Acute Flare.

19. 04 RISK FACTORS

20. 04 RISK FACTORS

21. 04 RISK FACTORS
AGE HBV infection are age dependent
Occurs in
- 1% of perinatal
- 10% of early childhood (1-5yrs of age)
- 30% of late childhood (>5yrs of age)
Development of chronic hepatitis B is inversely proportional to age
- 80-90% infected perinatally.
- 30% in early childhood.
- 5% in 6yrs of age.

22. 04 RISK GROUPS
- HIGH RISK GROUPS
Infection in surgeons are 50 times greater than in general population and
twice that of other physicians.
- Other risk group includes
Recipients of blood transfusion
Health care and lab personnel
Homosexuals, prostitutes, percutaneous drug abusers
Infants of HBV positive mothers
Solid organ transplants and immunocompromised persons.

23. 05 CLINICAL FEATURES
incubation period for hepatitis B from
30 to 180 days (mean, 8–12 weeks)
The prodromal symptoms of acute
viral hepatitis are systemic and quite
variable. Constitutional symptoms of
anorexia, nausea and vomiting,
fatigue, malaise, arthralgias,
myalgias, headache, photophobia,
pharyngitis, cough, and coryza may
precede the onset of jaundice by 1–2
weeks.
A low-grade fever between 38° and
39°C may accompany the
constitutional symptoms.
Dark urine and clay-colored stools

24. 05 CLINICAL FEATURES
With the onset of clinical jaundice, the constitutional prodromal symptoms
usually diminish.
The liver becomes enlarged and tender and may be associated with right
upper quadrant pain and discomfort.
Splenomegaly and cervical adenopathy are present in 10–20% of patients
with acute hepatitis.
During the recovery phase, constitutional symptoms disappear, but usually
some liver enlargement and abnormalities in liver biochemical tests are
still evident. Complete clinical and biochemical recovery is to be expected
3–4 months after the onset of jaundice in three-quarters of uncomplicated,
self-limited cases of hepatitis B .

25. 06 LABORATORY FEATURES
The serum aminotransferases aspartate aminotransferase (AST) and ALT
increase to a variable degree during the prodromal phase of acute viral
hepatitis and precede the rise in bilirubin level .
The level of these enzymes, however, does not correlate well with the
degree of liver cell damage.
Jaundice is usually visible in the sclera or skin when the serum bilirubin
value is >43 μmol/L (2.5 mg/dL).

26. 06 LABORATORY FEATURES
When jaundice appears, the serum bilirubin typically rises to levels ranging
from 85 to 340 μmol/L (5–20 mg/dL).
Bilirubin levels >340 μmol/L (20 mg/dL) extending and persisting late into
the course of viral hepatitis are more likely to be associated with severe
disease.
Neutropenia and lymphopenia are transient and are followed by a relative
lymphocytosis.
Measurement of the prothrombin time (PT) is important in patients with
acute viral hepatitis, because a prolonged value may reflect a severe
hepatic synthetic defect, signify extensive hepatocellular necrosis, and
indicate a worse prognosis.
In addition, a prolonged PT, low serum albumin level, hypoglycemia, and
very high serum bilirubin values suggest severe hepatocellular disease.

27. 06 LABORATORY FEATURES
A diagnosis of HBV infection can usually be made by detection of HBsAg in
serum. Infrequently, levels of HBsAg are too low to be detected during acute
HBV infection, even with contemporary, highly sensitive immunoassays. In
such cases, the diagnosis can be established by the presence of IgM anti-
HBc.
HBeAg. Its principal clinical usefulness is as an indicator of relative
infectivity.
testing for IgM anti-HBc may be useful to distinguish between acute or
recent infection (IgM anti-HBc-positive) and chronic HBV infection (IgM anti-
HBc-negative, IgG anti-HBc-positive).
After immunization with hepatitis B vaccine, which consists of HBsAg
alone, anti-HBs is the only serologic marker to appear.

29. 07 DIAGNOSTIC ALGORITHMS
Acute hepatitis — The diagnosis of acute hepatitis B is based upon the detection of HBsAg
and IgM anti-HBc
Rarely, patients present during the window period when HBsAg has become negative but
anti-HBs is not yet positive IgM anti-HBc is the sole marker of acute HBV infection
Past HBV infection — Previous HBV infection is characterized by the presence of anti-HBs
and IgG anti-HBc.
Immunity to HBV infection after vaccination is indicated by the presence of anti-HBs only.
Chronic HBV infection — The diagnosis of chronic HBV infection is based upon the
persistence of HBsAg for more than six months..

30. 08 CHRONIC HBV INFECTION
All patients with chronic HBV infection should be regularly monitored
because HBV DNA and ALT levels vary during the course of infection to
monitor for progression of liver disease. In addition, patients who are not
candidates for treatment at the time of presentation may become
candidates for treatment during follow-up.
HBeAg-negative patients who have normal serum ALT and low (<2000
international units/mL) or undetectable HBV DNA are considered to be in
an inactive carrier state.
These patients generally have a good prognosis and antiviral treatment is
not indicated.

31. 08 CHRONIC HBV INFECTION
However, serial tests are necessary to accurately differentiate them from
patients with HBeAg-negative chronic hepatitis who have fluctuating ALT
and/or HBV DNA levels. Thus, it is recommended that these patients have
repeat ALT +/- HBV DNA tests at three-month intervals during the first
year.
Patients who are truly inactive carriers should continue to be monitored
but at less frequent intervals.

34. 09 INTERPRETATIONS OF HBV SEROLOGY

35. 10 PHASES OF CHRONIC HBV
Heading

36. Heading

37. 11 DISTINGUISH BETWEEN ACUTE HBV AND A FLARE OF CHRONIC DISEASE
In areas of low HBV prevalence, such as the United Kingdom, a combination
of HBsAg positivity and features of acute hepatitis usually indicates acute
self-limiting hepatitis B infection.
In countries with high prevalence of hepatitis B the majority of infection is
acquired vertically during childhood and leads to chronicity rather than acute
infection.

38. 11 DISTINGUISH BETWEEN ACUTE HBV AND A FLARE OF CHRONIC
# Anti-HBc-IgM is typically found in acute HBV infection, however it can be
found in10-15% of patients with chronic HBV. This is especially true when
considering acute flares of chronic hepatitis.
The sensitivity and specificity for HBc-IgM to distinguish between acute HBV
and a chronic flare has been reported as low as 77% and 70% respectively.
# Flares of chronic HBV are typically associated with higher levels of HBV
DNA and AFP than acute self-limiting disease.

39. 12 ASSESSMENT OF LIVER DISEASE IN SECONDARY SPECIALIST CARE for
The initial test for liver disease in adults newly referred for assessment is transient
elastography.
Transient elastography (FibroScan) is a new, non
‐
invasive, rapid method allowing evaluation
of liver fibrosis by measurement of liver stiffness.
Interpretation of transient elastography score
1- ≥ 11 kPa antiviral treatment without a liver biopsy
2- between 6 and 10 kPa liver biopsy to confirm the level of fibrosis
3- < 6 kPa liver biopsy, if the: - Age < 30 years and HBV DNA > 2000 IU/ml and abnormal
ALT (≥30 IU/L for males and ≥ 19 IU/L for females) on 2 consecutive tests conducted 3
months apart.
4- < 6 kPa - NO liver biopsy, if the: - HBV DNA < 2000 IU/ml and normal ALT.
Offer annual reassessment of liver disease using transient elastography to adults who are
not taking antiviral treatment.

40. 13 PROPHYLAXIS
Current recommendations can be divided into those for preexposure and
postexposure prophylaxis.
For preexposure prophylaxis against hepatitis B in settings of frequent
exposure three IM (deltoid, not gluteal) injections of hepatitis B vaccine are
recommended at 0, 1, and 6 months.
Pregnancy is not a contraindication to vaccination
Marker of protection- anti- HBs titer more than 10 IU/ml

41. 13 PROPHYLAXIS
Hepatitis B vaccine is recommended for unvaccinated adults who are at risk for hepatitis B virus
infection, including:
1. All newborns
2. health workers exposed to blood
3. hemodialysis patients and staff
4. injection drug users
5. incarcerated inmates of correctional facilities
6. persons with multiple sexual partners or who have had a sexually transmitted disease
7. men who have sex with men
8. persons such as hemophiliacs who require long-term,
9. household and sexual contacts of persons with chronic HBV infection
10. persons living in or traveling extensively in endemic areas
11. unvaccinated children aged <18
12. persons born in countries with a prevalence of HBV infection ≥2%
13. persons aged <60 years with diabetes mellitus
14. persons with end-stage renal disease
15. persons with HIV infection

42. POST EXPOSURE
For unvaccinated persons sustaining an exposure to HBV, postexposure
prophylaxis with a combination of HBIG (for rapid achievement of high-titer
circulating anti-HBs) and hepatitis B vaccine (for achievement of long-
lasting immunity as well as its apparent efficacy in attenuating clinical
illness after exposure) is recommended.
For perinatal exposure of infants born to HBsAg-positive mothers, a single
dose of HBIG, 0.5 mL, should be administered IM in the thigh immediately
after birth, followed by a complete course of three injections of recombinant
hepatitis B vaccines approved for children to be started within the first 12 h
of life.

43. POST EXPOSURE
For those experiencing a direct percutaneous inoculation or transmucosal
exposure to HBsAg-positive blood or body fluids (e.g., accidental needle
stick, other mucosal penetration, or ingestion), a single IM dose of HBIG,
0.06 mL/kg, administered as soon after exposure as possible, is followed
by a complete course of hepatitis B vaccine to begin within the first week.
For pregnant mothers with high-level HBV DNA (>2 × 105 IU/mL), adding
antiviral nucleoside analogues (e.g., pregnancy class B tenofovir) during the
third trimester of pregnancy reduces perinatal transmission even further.
For persons exposed by sexual contact to a patient with acute hepatitis B, a
single IM dose of HBIG, 0.06 mL/kg, should be given within 14 days of
exposure, to be followed by a complete course of hepatitis B vaccine. When
both HBIG and hepatitis B vaccine are recommended, they may be given at
the same time but at separate sites

44. DURATION OF PROTECTION
The precise duration of protection afforded by hepatitis B vaccine is
unknown; however, ~80–90% of immunocompetent adult vaccinees retain
protective levels of anti-HBs for at least 5 years, and 60–80% for 10 years,
and protective antibody has been documented to last for at least two
decades after vaccination in infancy.
Thereafter and even after anti-HBs becomes undetectable, protection
persists against hepatitis B,

45. BOOSTER DOSE RECOMMENDATIONS
Currently, booster immunizations are not recommended routinely Except in
- immunosuppressed persons who have lost detectable anti-HBs
- immunocompetent persons who sustain percutaneous HBsAg-positive
inoculations after losing detectable antibody.
Specifically, for hemodialysis patients, annual anti-HBs testing is
recommended after vaccination; booster doses are recommended when
anti-HBs levels fall to <10 mIU/mL.

46. 14 FAILURE TO RESPOND
Failure to respond or respond poorly to 3 doses of the vaccine occur in
10-15% of adults.
Risk factors include:
1- age over 40 years 2- obesity,
3- smoking 4- alcohol excess 5-immunosuppression
• How to check response?
testing for anti-HBs levels only recommended for: those at risk of
occupational exposure (i.e. Healthcare workers) and patients with chronic
kidney disease.
In these patients anti-HBs should be checked 1-4 months after primary
immunisation

47. HOW TO INTERPRET ANTI-HBS LEVELS?

48. 15 TREATMENT
Most persons with acute hepatitis (especially hepatitis A, B, and E) recover
spontaneously and do not require specific antiviral therapy. In hepatitis B,
among previously healthy adults who present with clinically apparent acute
hepatitis, recovery occurs in ~99%; therefore, antiviral therapy is not likely to
improve the rate of recovery and is not required.
In fulminant hepatitis, the goal of therapy is to support the patient by
maintenance of fluid balance, support of circulation and respiration, control
of bleeding, correction of hypoglycemia, and treatment of other
complications of the comatose state in anticipation of liver regeneration and
repair. Protein intake should be restricted, and oral lactulose administered.
Acute Viral Hepatitis

49. MANAGEMENT OF CHRONIC HEPATITIS
Should be referred to a specialised centre to be managed and followed
by a sub-specialist
Indications of antiviral treatment in adults with chronic hepatitis B (NICE 2013)
1- age ≥ 30 years + HBV DNA > 2000 IU/ml + abnormal ALT (≥30 IU/L in males
≥19 IU/L in females) on 2 consecutive tests conducted 3 months apart.
2- Age < 30 years + HBV DNA > 2000 IU/ml + abnormal ALT if there is:
evidence of necro-inflammation or fibrosis on liver biopsy or a transient
elastography score > 6 kPa.
3- HBV DNA > 20,000 IU/ml + abnormal ALT regardless of age or the extent of
liver disease. (on 2 consecutive tests conducted 3 months apart)
4- cirrhosis + detectable HBV DNA, regardless of HBeAg status, HBV DNA and
ALT levels.
5- HBV DNA greater than 2000 IU/ml + evidence of necroi-nflammation or
fibrosis on liver biopsy.

50. 16 ANTIVIRAL DRUGS
The goals of treatment are HBeAg seroconversion, reduction in HBV-DNA
and normalisation of the LFTs.
The oral antiviral agents are more effective in reducing viral loads in
patients with e antigen-negative chronic hepatitis B than in those with e
antigen-positive chronic hepatitis B, as the pre-treatment viral loads are
lower.
Two different types of drug are used to treat hepatitis B:
direct-acting nucleoside/nucleotide analogues and pegylated interferon-
alfa.

51. Orally administered nucleoside/nucleotide antiviral agents are the
mainstay of therapy.
Entecavir and tenofovir are potent antivirals with a high barrier to genetic
resistance and so are the most appropriate first-line agents.
- Monotherapy with entecavir or tenofovir is substantially more effective
than lamivudine in reducing viral load in HBeAg-positive and HBeAg-
negative chronic hepatitis.
- Lamivudine Although effective, long-term therapy is often complicated
by the development of HBV-DNA polymerase mutants, which lead to viral
resistance. These occur after approximately 9 months and are
characterised by a rise in viral load during treatment.
NUCLEOSIDE/NUCLEOTIDE ANTIVIRAL AGENTS

52. Interferon-alfa
This is most effective in patients with a low viral load and serum
transaminases greater than twice the upper limit of normal,
Response rates are lower in HBeAg-negative chronic hepatitis, even when
patients are given longer courses of treatment. Interferon is contraindicated
in the presence of cirrhosis,
Liver transplantation
The survival rate after liver transplantation for end- stage liver disease
from HBV infection is greater than 90% at 1 year.
Recurrence of HBV infection in transplant recipients is prevented with HBV
immunoglobulin and/or oral antiviral therapy (Lamivudine).

53. 17 HEPATITIS B AND PREGNANCY
All pregnant women are offered screening for hepatitis B
Without intervention the vertical transmission rate is around 20%, which
increases to 90% if the woman is positive for HBeAg.
Babies born to mothers who are chronically infected with hepatitis B or to
mothers who've had acute hepatitis B during pregnancy should receive a
complete course of vaccination + hepatitis B immunoglobulin (nice 2013)
Offer tenofovir to women with HBV DNA greater than 10^7 IU/ml in the
third trimester to reduce the risk of transmission of HBV to the baby.
stopped at 4 to 12 weeks after the birth .
there is little evidence to suggest caesarean section reduces vertical
transmission rates
hepatitis B cannot be transmitted via breastfeeding (in contrast to HIV)

54. Q132
A 23-year old nurse is reviewed in occupational health following needle stick
injury from a man known to be a carrier of HBV. Which one of the following
would appear first during acute hepatitis B infection ?
A. HBsAg
B. HBeAg
C. Anti-HBs IgM
D. Anti-HBs IgG
E. HBcAg

55. Q155
A newly qualified staff nurse at the local hospital undergoes
vaccination against HBV.
The following results are obtained three months after
completion of primary course
Result Anti-HBs: 10-100 mIU/ml
What is the most appropriate course of action
A. Repeat course of hepatitis B vaccine (i.e. 3
doses)
B. Repeat anti-HBs level in three months time
C. Give a course of HBIG + one further dose
of hepatitis B vaccine
D. Give one further dose of hepatitis B vaccine

58. References
• Harrison's principles of internal medicine 21st edition
• Davidson's principles and practice of medicine 24th edition
• MKSAP 19 Gastroenterology and hepatology
• Step up to medicine Fourth edition
• Notes & Notes
• Uptodate