Hepatitis B Acute & Chronic Infections

IgM against core antigen [Ref Harrison 16^th/e p. 1832]

• What is chronic active hepatitis ? . Chronic hepatitis B is usually classified by histological features such as grade and stage.
• The other way to classify chronic hepatitis is based on relative level of HBV replication :A) A Replicative phase of chronic hepatitis B is known as chronic active hepatitisQ.

. Characterized by the presence of the markers of HBV replication such as HBeAg and HBVDNA.

B) Non replicative phase of chronic hepatitis

• This is characterized by the absence of conventional markers of HBV replication i.e., (HBeAg and HBVDNA).

Thus the serological markers of chronic active hepatitis B are 😕

• HBsAg
• HBeAg
• HBVDNA
• IgGHBcAg

“IgM AntiHBcAg is never^e seen in chronic hepatits, its presence confirms that hepatitis is acute”.

Antibodies to HBcAg

Antibodies to HBcAg are not protective but we can use them to understand how long the infection has been going.

• IgM antiHBcAg Acute infection
• 1gM antiHBcAg = Chronic infection

The role of IgM antillBc in the diagnosis

• The presence of HBsAg with or without 1gM anti HBc represents HBV infection.e
• If IgM anti HBc is present, the HBV infection is considered acute and if IgM antiHBc is absent the infection is considered chronic.e
• A diagnosis of acute hepatitis can be made even in the absence of HBsAg if IgM Anti HBc is detectable.

DNA polymerase [Ref: Harrison 16^1h/e p. 1933, 1934; 16^th/e p. 1832]

“DNA polymerase activity, HBVDNA, HBeAg which are representative of the vireinic stage of hepatitis B occur early in the incubation period concurrently or shortly after the first appearance of HBsAg” –

Jawetz – 19% p. 475.

• DNA polymerase is a marker for active viral replication.
• It is not exclusively associated with acute hepatitis B.
• It is also seen in chronic hepatitis B when there is active viral replication in chronic hepatitis (Chronic active hepatitis).
• But since active viral replication is usually associated with acute hepatitis, DNA polymerase is usually associated with seen in acute heptitis B.

Serological markers of Acute Hepatitis B infection

• HBsAg appears before the onset of symptoms^e, peaks during overt disease and then declines to undetectable levels in 3-6 months.

HBeAg, HBV-DNA and DNA polymerase appear in the serum soon after HBsAg and all signify active viral replication.

• IgM anti-HBc becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of elevation of serum aminotransferases. Over months the 1gM antibody is replaced by IgG Anti HBc (wizen infection becomes chronic)
• Anti HBS is detectable shortly after the disappearance of HBeAg implying that the acute infection has peaked and the disease is on the wane.

Hepatitis core antigen never appears in the serum.

The association between chronic HBV infection and glomerular diseases was first described in 1971.

• Membranous nephropathy, 
• Minimal change nephropathy, 
• Mesangial proliferative glomerulonephritis, 
• Membranoproliferative glomerulonephritis
• IgA nephropathy

HBV can cause renal damage in many ways. The different pathogenesis are described as the cause for it. They are,

Patient in the question is positive for HBsAg and HBeAg, so he is more likely to be highly infectious and must be associated with the presence of Hepatitis B virions and a detectable HBV DNA.

Ref: Harrisons Internal Medicine, 18th Edition, Chapter 304, Page 2540 ; Review of Medical Microbiology and Immunology By Warren Levinson, 11th Edition, Chapter 41

Patient in the question stem is showing features of chronic active hepatitis. HBeAg  is negative due to the pre core mutant variant of hepatitis B. Pre core mutation is responsible for the decrease or non production of HBeAg. Such mutations often occur at the time of seroconversion from HBe Ag to anti HBe Ab.

Ref: Digestive Involvement in Systemic Autoimmune Diseasesedited by Josep Font, Page 192; Detection of Bacteria, Viruses, Parasites and Fungi: Bioterrorism Prevention By Mariapia Viola Magni, Page 248; Sherlock’s Diseases of the Liver and Biliary System edited by James S. DooleypGE 367, 8.

Chronic hepatitis B:

Ans. is ‘c’ i.e., Hepatic adenoma 

Complications of Acute HBV infection

.  Fulminant hepatitis                                                                                      . Cirrhosis

.  Hepatocellular carcinoma                                                                          . Chronic hepatitis

. Papular acrodermatitis of child hood (Gianotti – crosti syndrome)     . Glomerulonephritis

.  Essential mixed cryoglobulinemia (more common with HCV)

.  Polyarteritis nodosa (PAN) may be associated with HBV infection.

Remember

Hepatocellular carcinoma is the only vaccine preventable cancer.

Ans. is ‘a’ i.e., Ig M anti-HBc antibody 

.  Has been explained

.  Ig M anti-HBc antibody is the marker of acute or recent HBV infection.

Ans. is ‘c’ i.e., Intramuscular Deltoid 

Prophalyxis against HBV

.   Both passive and active immunization are available for HBV infection prophylaxis.

.   Passive prophylaxis is by hepatitis B immune globulin (HBIG).

.   Active immunization is by recombinant hepatitis B vaccine.

.  These are two recombinant vaccines :

1. Recombivax – HB
2. Engerix – B

• Vaccine is given intramuscular into the deltoid or in infants into the anterolateral aspect of thigh. Gluteal injection is not recommended as it may result in poor immune response.

.   Three doses are given at 0, 1 and 6 months.

.  For pre exposure prophylaxis only hepatitis B vaccine is given.

.  For post exposure prophylaxis combination of HBIG and hepatitis B vaccine is recommended.

• For perinatal exposure single dose of HBIG at birth along with complete course of vaccination is recommended. First dose of vaccine should be given within 12 hours after birth.

Ans. is ‘b’ i.e., Ground glass hepatocytes

• Ground glass hepatocytes are large hepatocytes containing surface antigen. Their cytoplasm is ground glass in appearance

o These cells are seen in chronic hepatitis (not acute hepatitis)

o Ground glass hepatocytes can be identified histochemically with orcein or aldehyde fuschin stain.

Pathological features of acute viral hepatitis

1. Panlobular infiltration of mononuclear cells

This mononuclear infiltration primarily consists of —> Lymphocytes, Plasma cells, Eosinophils

Inflammatory infiltrate may spill over into the adjacent parenchyma to cause necrosis of periportal hepatocytes -3 interface hepatitis, can occur in both acute and chronic hepatitis.

2. Hepatic cell damage – It consits of

(a)     Hepatic cell necrosis – The necrosis is usually focal or centirzonal.

Sometimes severe necrosis such as bridging or subacute hepatic necorsis occurs.

(b)     Ballooning of cells — Damaged cells show diffuse swelling known as ballooning degeneration.

(c)     Acidophilic degeneration of hepatocytes – In this single necrotic liver cell has coagulated pink cytoplasm and it shows pyknosis or karyolysis. These are called councilman bodies.

(d)     Cell dropout

3. Hyperplasia of kupffer cells

4. Variable degree of cholestasis with brown pigmentation of hepatocytes.

5. Hepatic cell regeneration – It is indicated by increased mitotic figures, rosette or pseudoacinar formation and multi nucleated cells.

6. Lobular disarray —> Loss of normal lobular architecture.

o Note that these morphological lesions are similar in all types of viral hepatitis.

o A few histological changes may be indicative of particular type of virus.

1.In hepatitis C the histological lesion is characterized by –

a Relative paucity of inflammation

           Marked increase in activation of sinusoidal lining cells.

           Presence of lymphoid aggregates

           Presence offal Macrovesicular steatosis

           Bile duct lesions.

2.In Hepatitis D -* Microvesicular steatosis occurs.

3.In Hepatitis E —)Marked cholestasis occurs.

Ans. is ‘b’ i.e., HBV

o HBV-infected hepatocytes may show a cytoplasm packed with spheres and tubules of HBs Ag, producing a finely granular cytoplasm (“ground-glass hepatocytes”).

Ans. is ‘d’ i.e., Cholangiocarcinoma

Ans. is `b’ i.e., HBs positive and Hbe Ag positive

Perinatal transmission of HBV

o Most important risk factor that determines perinatal transmission is HBe Ag. HBs Ag carrier mothers who are HBe Ag positive almost invariably (> 90%) transmit hepatitis B infection to their offspring, where as carrier mothers with anti HBe rarely (10 to 15%) infect their offspring.

o Most common time of perinatal transmission is at the time of delivery.

o Most of the infected neonates are asymptomatic carrier with increased chances of chronic hepatitis and hepatocellular carcinoma.

Ans. is ‘a’ i.e., Both active and passive immunization soon after birth 

Immunization of infants born to HbsAg positive women.

o These infants should receive both active and passive immunization soon after birth.

The first dose of active immunization should be accompanied by administration of .5 nil of HBIG as

soon after delivery is possible, because the effectiveness decreases rapidly with increased time after birth.

o Subsequent doses of active immunization should be given at 1-2mo, and 6 mo of age. 

Ans. is ‘c’ i.e. HBV predisposes

• Most common cancers in the world are —> Lung > Breast > Colorectal.
• As already stated before, HCC presents quite late and thus only 15-20% cancers are resectable. Most patients with unresectable lesions die within a year after diagnosis.

Answer is D (HDV/HBV Superinfection)

HDV superinfection of chronic Hepatitis B is associated with a 20 percent risk of progression to fulminant hepatitis and Acute Hepatic Failure.

Tendency to cause acute liver failure (fulminant infection) is highest with HDV Superinfection on Chronic Hepatitis B and Hepatitis E infection in pregnant women (up to 20 percent)

Note:

• Hepatitis E is the most common cause of Acute Liver Failure in India
• Hepatitis B remains the most common viral agent responsible for Acute Liver Failure Worldwide Although Hepatitis E has a higher tendency to cause fulminant infection (1-2 %) in comparison to Hepatitis B infection (Up-to 1%), Hepatitis B is the most common cause of fulminant infection overall since the overall incidence of Hepatitis B Hepatitis is higher than the incidence of Hepatitis E Hepatitis
• Tendency to cause acute liver failure (fidminant infection) is highest with HDV Superinfection on Chronic Hepatitis B and Hepatitis E infection in Pregnant women (up to 20 percent)

Answer is B (HBV pre-core mutant)

Evidence of chronic active hepatitis B (suggested by elevated liver enzymes) in a patients with detectable HBV DNA but negative HBe Ag suggests a diagnosis of precore mutant chronic hepatitis B

Precore mutant chronic hepatitis B

• Precore mutant form of chronic hepatitis B represents an infection with a molecular variant of the hepatitis B virus that results in an unusual serologic — clinical profile.
• Such patients have severe chronic hepatitis B infection with detectable HBV DNA levels, but HBe Ag antigen is typically negative
• This results from an infection with an HBV mutant that contains an alteration in the precore regions rendering the virus incapable of encoding HBe Ag
• Patients with such mutations in the precore region are unable to secrete HBc Ag, have a negative HBe Ag phenotype but tend to have severe liver disease that progresses more rapidly to cirrhosis
• Characteristic’ of such HBe Ag negative (precore mutant) chronic  hepatitis B are lower levels of HBV DNA (< 105 copies /m1) and one of several patterns of aminotransferase activity — persistent elevation, periodic fluctuation above the normal range and periodic fluctuations between the normal and elevated range
• HBe Ag negative chronic hepatitis B with mutation in the pre-core region is now the most frequently encountered form of hepatitis B in the Mediterranean countries and in Europe.

Answer is A (Inactive HBV carrier)

Absence of clinical signs and symptoms of liver damage and normal liver enzymes in an HBs Ag positive individual with otherwise unremarkable serological tests suggests a diagnosis of Inactive HBV carrier state.

‘An inactive hepatitis B carrier is defined as one with HBs Ag in serum hut without HBe Ag with normal liver function tests and with low/ undetectable levels of HBV DNA (< 10³-10⁴ virions/ml) – ‘Blue Prints Pocket Gastroenterology’ by Grover (Lippincott Williams) 1^st (2007) /114

Chronic Hepatitis B carriers (HBs Ag + ye with IgG Anti HBc)

Chronic Hepatitis B virus carriers can be divided into two categories based on activity of the virus and evidence of liver damage

Inactive HBs Ag Carrier state

• Patients with negligible virus replication (HBV DNA levels < 10³ virions/m1) and /or no clinical signs and symptoms of liver damage and normal liver enzyme levels are characterized as inactive HBV carriers Inactive HBV carriers harbor Hepatitis B virus antigen (HBs Ag), but are clinically asymptomatic, have a normal physical examination with normal liver enzymes (AST & ALT). HBe Ag is typically negative and levels of HBV DNA are less than 10³-10⁴ virions/ml
• Such patients have minimal (if any) liver inflammation or damage, and usually live a normal life. However compared to the general population these patients remain at risk for hepatocellular carcinoma
• Treatment is currently not recommended for
• Inactive HBV carrier. However regular observation is advised as there is a risk for reactivation of virus.

Chronic Hepatitis B (Active)

Patients with active virus replication ( HBV DNA levels > 10³ -10⁴ virions/ml) and /or clinical signs and symptoms of liver damage or elevated liver enzyme levels are characterized as chronic hepatitis B patients.

Depending on the presence or absence of HBe Ag two type of chronic (active) hepatitis B may be identified.

HBe Ag positive chronic hepatitis B

These HBs Ag positive, individuals are also positive for HBe Ag and show detectable HBV DNA levels. Such patients are in the replicative phase of chronic hepatitis B infection, have persistently or intermittently elevated liver enzymes and liver biopsy results typically reveals inflammation and damage

Patients with chronic (active) hepatitis B may become inactive (relatively non replicative) over time (rate of _L-10 % per year) by becoming negative for HBe Ag and HBV DNA (HBV DNA < 10' - 10⁴) virions/ml) Liver injury tend to subside in such patients and these may then be characterized as ‘inactive carriers’

HBe Ag negative chronic hepatitis B (Precore mutant)

Such HBs Ag positive individuals are negative for HBe Ag but show detectable HBV DNA levels. Such patients are also in the replicative phase of chronic hepatitis B (despite negative HBe Ag) and have persistently or intermittently elevated liver enzymes and liver biopsy results typically reveal severe inflammation and damage

Negative HBe Ag Status results from a mutant strain of hepatitis B that is characterized by the _.failure of the virus to make the hepatitis B ‘e’ antigen (HBe Ag). This mutation is called the `precore’ mutation as it prevents the translation of a precore protein to prevent HBe antigen production.

This mutation does not however affect the ability of the virus to replicate

Answer is A (DNA polymerase)

DNA polymerase is a marker for active viral replication.

DNA polymerase are usually associated with Acute viral hepatitis B when there is active viral replication and hence DNA polymerase is the single best answer amongst the options provided

Note that although DNA polymerase is often present in acute Hepatitis B infection, its presence suggests active virus replication (like HbeAg, HBV DNA) and it should not be used as a laboratory marker for acute hepatitis B infection.

`During the acute episode of disease when there is active viral replication large amounts of HB.sAg and Hepatic B virus DNA can be detected in the serum as can fully developed virions and high levels of DNA polymerase and HBeAg’-Current Diagnosis and Treatment in Infections Disease/437

Answer is D (HBV-DNA estimation)

Like Hbe Ag, serum HBV DNA is an indicator of HBV replication, but tests for^. HBV DNA are more sensitive and quantitative- Harrison 161h/1832

The marker HBV DNA is useful in following the course of HBV replication and thus deciding need for antiviral chemotherapy.

Interferon therapy would be started after adjudging its need as indicated by HBV DNA testing.

Liver biopsy would be too radical at this stage.

Answer is B (Acute Viral Hepatitis B – Antiviral therapy):

Acute Viral Hepatitis B is not an indication of Antiviral therapy. Antiviral therapy is not indicated for Acute Hepatitis B.

Acute Hepatitis B is not an approved indication for Antiviral Therapy

In the vast majority of patients Acute Hepatitis B is a self limiting disease that results in viral elimination and complete healing.

‘In Hepatitis B among previously healthy adults who present with clinically apparent hepatitis, recovery occurs in – 99%; therefore antiviral therapy is not likely to improve the rate of recovery and is not required’- Harrison ‘s 17’h/1946

‘The administration of Antiviral therapy (lami^yudine) to patients with acute hepatitis B may slow the development of protective Anti- HBs titres. Therefore antiviral treatment is not recommended in patients with uncomplicated acute viral hepatitis B’ – Clinical Hepatology (Springer, 2010) /761

Note (Harrison ‘s 17^th /1946; Clinical Hepatology (2010)/761)

Antiviral therapy with nucleos(t)ide analogs might be considered for fewer than I% of patients with acute viral hepatitis B who present with a Alininant clinical course. Although at present severe/fuhninant acute hepatitis B is not an approved indication of antiviral therapy and there is no data to support such an approach most authorities would recommended institution of antiviral therapy for severe acute Hepatitis B

Answer is D (Gall stone disease)

Gallstone disease has not been mentioned in the list for extrahepatic manifestations of Hepatitis B

Extrahepatic manifestations in viral hepatitis B:

• Aplastic Anemia
• Cryoglobulinaemia
• Diabetes mellitus
• Dermatomyositis-like syndrome
• Gianotti- Crosti syndrome
• Glomerulonephritis
• Gui!lain- Barre syndrome
• Myasthenia gravis
• Pericarditis and myocarditis
• Pancreatitis
• Peripheral Neuropathy
• Polyarleritis Nodosa
• Polyarthritis
• Polymyalgia rheumatica
• Polymyositis
• Porphyria cutanea tarda
• Psychosis
• Raynaud’s syndrome
• Serum sickness like illness
• Splenomegaly and lymph node enlargement
• Skin alterations
• Thrombopenic^. purpura
• Thyroiditis
• Urticaria

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. C: 0, 1, 6 months

Children under 10 years should be given half of the adult doses at the same intervals or at 6, 10 and 14 weeks as per Indian National Immunization Schedule.

For greater reliability of absorption, deltoid is the preferred for injection as gluteal injection often results in deposition of the vaccine in fat rather than in muscle.

For Children under 2 years of age, anterolateral aspect of thigh is used as vaccination site.

Ans. is ‘c’ i.e., HBV

OPV and measles vaccines are stored in deep freezers. (Note : Yellow fever vaccine is also freez dried, but is not used in India).

Vaccine which must be stored in the cold part but never allowed to freez.

• Typhoid
• DPT
• TT 
• Hepatitis B
• DT
• BCG
• Diluents

Ans. is ‘c’ i.e., Polyatrteritis nodosa

The hepatitis B surface antigen is present in 25% of patients with Polyarteritis Nodosa.

Hepatitis C antibody is present in patients with essential mixed cryoglobinuria and rarely in patients with poly arteritis nodosa.

Ans. is ‘b’ i.e., HBV DNA

• In patients with chronic hepatitis B infection the level of HBV DNA correlates with the level of liver injury and risk of progression of disease.

Ans is  b

1 in this graph is HBV DNA

Patient in the question stem is showing features of chronic active hepatitis. HBeAg  is negative due to the pre core mutant variant of hepatitis B. Pre core mutation is responsible for the decrease or non production of HBeAg. Such mutations often occur at the time of seroconversion from HBe Ag to anti HBe Ab.