Hepatitis B Virus

Anti HBs is the protective antibody , It is present either after recovery from hepatitis B or immunization.

Anti HBsAg REF: APPENDIX-28 for “MARKERS OF HEPATITIS-B”

“Positive Anti HBsAg determines the efficacy of hepatitis B vaccination

The first antibody to appear is the antibody to hepatitis B core antigen (HBcAg) (anti-HBc). Initially, it is of the immunoglobulin M (IgM) class. Indeed, the presence of IgM anti-HBc is diagnostic for acute HBV infection.

Weeks later, IgM anti-HBc disappears, and IgG anti-HBc is detected. Anti-HBc may be present for life. 

Anti HBc REF: Harrison’s 17ed chapter 298, http://www.cdc.gov/hepatitis/HBV/PDFs/SerologicChartv8.pdf http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index3.html#serological markers

See APPENDIX-28 for “MARKERS OF HEPATITIS-B”

Recumbent means “Low level” chronic infection

Stages of chronic Hepatitis B infection

1. Immunotolerant phase: Patients often had high amount of Hepatitis B virus but despite that, there is little inflammation in the liver and patients’ liver panel are normal. It is because patient’s immune system does not recognize the virus.
2. Immunoclearance phase: Patients’ immune system started to recognize the virus and begin to kill the viruses. As Hepatitis B virus live in the liver, such killing also causes the liver cells to die. Patients often has abnormal liver panel at this stage. If this stage persists for prolonged period, patients progress to complications faster.
3. Inactive carrier stage: At this stage, patients have low amount of Hepatitis B virus and there is little liver damage. Risk of progression decreases but may still occur.
4. Reactivation phase: At this stage, patients’ Hepatitis B virus becomes reactivated and increases in amount, with active liver damage.

Highest transmission of hepatitis B from mother to fetus occurs if the mother is infected during 3rd trimester (90%). Transmission is high from those mothers who are seropositive to hepatitis B surface antigen (HBsAg) and HbeAg. Risk of transmission is only 10% in first trimester.

Hepatitis B virus is transmitted by parenteral route, sexual contact, vertical transmission and also through breast milk. Neonatal transmission mainly occur at or around the time of birth through mixing of maternal blood and genital secretions.

It can be diagnosed by the detection of HBsAg and HBeAg and antibody to hepatitis B core antigen (HBcAg). They are at high risk of developing chronic active hepatitis, cirrhosis and hepatocellular carcinoma.

Ref: Textbook of Obstetrics By D. C Dutta, 6th Edition, Page 291-2

Ans:D.)90%

Vertical Transmission of Hepatitis B

• In patients with acute hepatitis B vertical transmission occurs in up to 10% of neonates when infection occurs in the first trimester and in 80 -90% of neonates when acute infection occurs in the third trimester.
• In women who are seropositive for both HBsAg and HBeAg vertical transmission is approximately 90%. 
• 10-20% of women seropositive for HBsAg transmit the virus to their neonates in the absence of immunoprophylaxis.
• The increased risk of transmission with HBeAg positive status is due to high titres of HBV in these women.

However universal precaution is not needed for breast milk (no occupational hazard), Human breast milk has been implicated in perinatal transmission of HIV, and HBsAg has been found in the milk of mothers infected with HBV (REF: JAMA 1988; 259:1353-6. Lifson AR, Bond WW, Petersen NJ, Gravelle CR, Favero MS. Hepatitis B virus in peritoneal dialysis fluid: A potential hazard. Dialysis and Transplantation 1982; 11:592-600.)

Harrison says that serum, semen and saliva are most infectious for hepatitis B transmission.
Robbin’s 7th ed says that hepatitis B antigen is present in all body secretions except stools
CDC GUIDELINES: (REF: http://www.cdc.gov/mmwr/preview/mmwrhtml/00000039.htm)

Extension of blood and body fluid precautions to all patients is referred to as “Universal Blood and Body Fluid Precautions” or “Universal Precautions.” Under universal precautions, blood and certain body fluids of all patients are considered potentially infectious for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and other bloodborne pathogens.

BODY FLUIDS TO WHICH UNIVERSAL PRECAUTIONS APPLY:

•Universal precautions apply to blood and to other body fluids containing visible blood.

•Blood is the single most important source of HIV, HBV, and other bloodborne pathogens in the occupational setting

•Universal precautions also apply to tissues and to the following fluids: semen and vaginal secretions, cerebrospinal fluid (CSF), synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid.

BODY FLUIDS TO WHICH UNIVERSAL PRECAUTIONS DO NOT APPLY:

•Universal precautions do not apply to feces, nasal secretions, sputum, sweat, tears, urine, and vomitus unless they contain visible blood

•The risk of transmission of HIV and HBV from these fluids and materials is extremely low or nonexistent.

•Human breast milk has been implicated in perinatal transmission of HIV, and HBsAg has been found in the milk of mothers infected with HBV (10, 13). However, occupational exposure to human breast milk has not been implicated in the transmission of HIV nor HBV infection to health-care workers.

•Whereas universal precautions do not apply to human breast milk, gloves may be worn by health-care workers in situations where exposures to breast milk might be frequent, for example, in breast milk banking.

• Universal precautions do not apply to saliva. Saliva of some persons infected with HBV has been shown to contain HBV-DNA at concentrations 1/1,000 to 1/10,000 of that found in the infected person’s serum. HBsAg-positive saliva has been shown to be infectious when injected into experimental animals and in human bite exposures

HBsAg in the serum is the first evidence of infection, HBeAg indicates viral replication and infectivity. Patients who are HBsAg and HBeAg positive indicates that they are highly infective. Anti HBsAg appear in individuals after clearence of HBsAg and is also present in individuals after successful vaccination.

Reference:
Harrison’s Principles of Internal Medicine 18th edition chapter 304.

Ans. is ‘a’ i.e., 45 to 180 days

Ans. is ‘b’ i.e., Ayw; ‘c’ i.e., Adr

Antigenic components

.   HBV contains two different antigenic components :

1. Common group reactive antigen ‘a’
2. Two pairs of type specific antigen d-y and w-r, only one member of each pair being present at a time.

.    HBV can be divided into four major antigenic types :

1. adw                         3. ayw
2. adr                          4. ayr

.    ayw is common in Western and Northern India.

.    adr is prevalent in South and East India.

Ans. is ‘c’ i.e., P gene

Ans. is ‘a’ i.e., P gene

• P gene is the largest gene.

Ans. is ‘b’ i.e., Pasteurized albumin

Transmission of HBV

. HBV infection is transmitted by

– Transfusion of blood or blood products.

– Sexual transmission

– Vertical transmission from mother to child

–        Percutaneous transmission (eg – needle punctures)

.  Blood is the most important source of infection.

.   Virus is also present in saliva, breast milk, semen, vaginal secretions, urine, bile and feces. Of these, semen and saliva are known to transmit the infection.

.  Perinatal transmission occurs mostly at the time of delivery.

Ans. is ‘b’ i.e., Transmitted by feco-oral route 

• HBV is not transmitted by feco-oral route.
• All other options are true.

Ans. is ‘d’ i.e., Least chance of chronicity 

. Least chances of chronicity are with HAV and HEV.

. Maximum chance of chronicity is with HCV.

.  90% of infants infected with HBV, become chronically infected.

Remember

By definition, HBV chronic carriers are those in whom HBs Ag persists for more than 6 months.

Ans. is ‘b’ i.e., Anti HBsAg 

 Anti HBs Ag

. It becomes detectable in blood when HBs Ag disappears.

.  Anti HBs Ag is protective antibody.

.  It is the only serological marker, present after immunization.

Ans. is b’ i.e., HBcAg 

.    HBc Ag is not demonstrable in the circulation because it is enclosed within the HBs Ag coat.

.    HBc Ag remain in the hepatocyte, where it can readily be detectable by immunohistochemical staining.

Ans. is ‘b’ i.e., HBsAg + Core antibody 

In acute hepatitis following serological markers are present :

1. HBs Ag
2. Ig M anti HBc Ag (in recent infection) or IgG anti HBc Ag (in remote infection).
3. HBe Ag (with high infectivity) or Anti HBe Ag (with low infectivity).

Ans. is ‘d’ i.e., Anti HBc 

. Anti HBc is used as epidemiological market because :‑

.  It is positive in all acute and chronic cases

. It is a “reliable marker of infection, past or current “

.  There is controversy over this question, in most of the Guides answer is HBs Ag. But read the following statement of Harrison,

.  In 1-5% of patients with acute HBV infection, levels of HBs Ag are too low to be detected, in such cases, the presence of Ig M anti-HBc establish the diagnosis of acute hepatitis B – 

. So HBs Ag can not be used for epidemiologic study.

Ans. is ‘a’ i.e., HBeAg 

• HBeAg is an indicator of active intrahepatic replication and high infectivity.
• It is a qualitative marker of HBV replication.

Ans. is ‘a’ i.e., HBe antigen

Ans is ‘c’ i.e., Hbs Ag

o Immune complex mediated tissue damage is the cause of glomerulonephritis in HBV infection.

o Immune complex consists Hbs Ag and antiHBs.

o Hbs Ag is a structural component HBV, while Anti Hbs Ag is formed by the host.

o So, Hbs Ag is the component of HBV that is responsible for glomerulonephritis.

Ans. is’ d i.e., Blood transfusion 

“Children usually acquire infection indirectly, through parenteral route from hepatitis B contaminated blood transfusion”.

Other modes of transmission in children : –

i)    Sharing of contaminated hypodermic needles used for multiple doses of infection.

ii)     Shaving razors.

iii)      Sexual contact Adolescent boys & girls.

Answer is B (IgM antibody to Hb_c Ag):

Acute injection is best indicated by an IgM anti Hb, Ag.

Serology of Hepatitis B

Hbs Ag would be positive even in chronic injection and heriee cannot be used to establish a diagnosis of acute Hepatitis B infection.

Window period is a period during recovery phase when both of these are negative and the diagnosis may be missed if test includes only Hbs Ag and Anti Hbs Ag.

Answer is A (HBV DNA)

HBV DNA is the most sensitive marker of active Hepatitis B virus replication

`HBV DNA is the most sensitive marker of virus replication. The detection of HBV DNA as the most sensitive marker of virus replication end as such proof of infectivity has replaced the determination of DNA polymerase’ — ‘Hepatology’ by Kuntz 3rd/121

`The gold standard for confirmation of viral replication is qualitative HBV DNA detection’

— ‘Viral Infections & Treatment’ by Weigmann (2003)/225

Markers for HBV Replication

HBV DNA^e > HBV DNA polymerase^e > HBe Age

Answer is A and D (HBsAg)

Acute Hepatitis B is characteristically diagnosed by the presence of IgM anti HBc with HBs Ag. Presence of IgM anti HBc without IlBs Ag mar suggest acute hepatitis in the window period.

Answer is None:

The next hest investigation to confirm the diagnosis of acute hepatitis B infection should be serological measurement of IgM anti, HBc antibody, which is not provided amongst the options (probably HBc Ag has been misprinted as HBeAg) Neither of the options provided (HBeAg. Anti IlbeAg, antillBeAg (Igni) or HBV DNA) can confirm a diagnosis of Acute Hepatitis.

Answer is B (HBs Ag + HBe Ag)

Thus, the presence of the above two markers indicate an infection with hepatitis B virus and high infectivity. Q Whether the infection is acute or chronic can, however, only be commented if status of anti-HBe marker is dear.

Answer is D (HBs Ag)

HBsAg is not a marker for active HBV Replication. Serological markers for active viral replication include HBe Ag, presence of DNA polymerase and circulating HBV DNA.

Answer is C (‘P’ gene):

The reverse transcriptase activity is a property of DNA polymerase which is coded by gene.

Genomic structure of Hepatitis B:

Answer is A (Vertical Transmission is more common than horizontal transmission in non-endemic areas)

Vertical transmission is more common that horizontal transmission in endemic Areas (not in non-endemic areas) Age of onset determines prognosis

Period of communicability lasts several months

Virus can be detected in blood one month before jaundice

‘Circulating HBsAg precedes elevation of aminotransferases and clinical symptoms (jaundice) by 2-6 weeks and remains detectable during the entire icteric or s^ymptomatic phase of acute ‘Hepatitis B’ and beyond’ – Harrison ‘s 17^th /1933

Vertical transmission is more common in Endemic areas

‘Perinatal transmission (vertical) is uncommon in North America and Europe (Non-Endemic areas) hut occurs with great frequency and is the most common mode of HBV perpetuation in the Far East and developing countries (Endemic areas)’ – Harrison ‘s 17th/1940,1947

Answer is B (↑  HBV DNA and ↑  ALT)

Antiviral therapy with interferon is indicated in patients with active viral replication (i^s HBV DNA) and elevated ALT levels

Patient with active DNA replication (T HBV DNA) and cirrhosis (compensated or decompensated) should not be treated with Interferon therapy These patients should he treated with other oral agents and IFN

Indications for Interferon Therapy

Chronic^. Hepatitis with ^“iHBV DNA and Elevated LFT

Ans. A: HBsAg

Ans. is ‘b’ i.e., C

Genes & gene products

• The genome of HBV is made of circular DNA, but it is unusual because the DNA is not fully double stranded —› one of the strands is incomplete and other is complete → partially double stranded DNA.
• There are four known genes encoded by genome —› ‘C’ , X’, `P’ ,’S’.

Ans. is ‘b’ i.e., HBV

• The hepatitis B virus (HBV) is a small enveloped DNA virus that causes acute and chronic hepatitis. HBV infection is a world health problem, with 350 million chronically infected people at increased risk of developing liver disease and hepatocellular carcinoma (HCC).
• Oncoviruses are implicated in approximately 12% of all human cancers. 
• A large number of the world’s population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer.
• In the absence of cytopathic effect in infected hepatocytes, the oncogenic role of HBV might involve a combination of direct and indirect effects of the virus during the multistep process of liver carcinogenesis. 
• Liver inflammation and hepatocyte proliferation driven by host immune responses are recognized driving forces of liver cell transformation. Genetic and epigenetic alterations can also result from viral DNA integration into host chromosomes and from prolonged expression of viral gene products.
• Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV).

Ans. is ‘c’ i.e., HbsAg + HBeAg + HBV DNA

• In HBV infection, there are two types of carriers :

Super Carriers

• High titre of HBsAg, HBe Ag, DNA polymerase and HBV in the circulation

• Highly infective

Simple carriers

• Low titre of HBsAg with negative HBeAg, DNA polymerase and HBV

• Have low infectivity

Ans. is ‘b’ i.e., HBV

Many viruses have a propensity to cause latent infections. The majority of these viruses are from the family of Herpesviridae: herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus (VZV), Epstein–Barr virus (EBV), CMV, human herpesvirus (HHV)-6, HHV-7 and Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV)-8.

Other are- HBV, HCV, Rabies Virus, Measles Virus, HIV, HTLV, HPV, HSV etc

Ans. is ‘a’ i.e., H BeAg