Five main types of hepatitis

- A & E (2 con đầu và cuối): lây theo đường phân miệng (fecal-oral), no envelope và
NOT develop into chronic
- 3 con ở giữa (B→D):
+ Blood + Body fluid transmission.
+ Via mucus and percutaneous contact.
+ Có chronic progression.
+ Có envelope.
- Vaccine:
+ Chỉ A và B có vaccine.
+ Để phòng HDV thì dùng vaccine cho HBV (B và D là BuDdy)
+ HEV thì chỉ có TQ có vaccine.
- Only HBV:
+ Family: Hepadnaviridae
+ Circular, partially double DNA. ⇒ Group VII Baltimore.
 + The rest has RNA.

Structure:
- Có 3 dạng:
+ Tiểu thể Dane - có capsid (with genome inside), đường kính 42 nm. (7-nm outer shell
and a 27- nm inner core)
+ 2 tiểu thể nhỏ không hoàn chỉnh (không capsid) - với đường kính 22nm. Shape: sphere
and filament.
- Cấu tạo:
+ Envelope: lớp vỏ ngoài.
+ Capsid: vỏ (riêng HBV: core = capsid).=> Kháng nguyên core thực chất là kháng nguyên
capsid nha (HbcAg).
- Thuyết âm mưu của 2 tiểu thể nhỏ: đánh lạc hướng antibody để tiểu thể Dane sống sót.

Viral genome
 -

+ Circular DS-DNA: Genome bị khuyết sợi dương. Sợi âm gắn với DNA polymerase:
vừa phiên mã ngược, vừa nhân lên, vừa phá huỷ template DNA gắn với RNA.
+ Pre C và C tổng hợp thành protein E (HBeAg). → sau này có precore mutation to stop
producing HBeAg → immune invasion.
+ Gene X → mã hoá protein X (HBx) ⇒ liên quan đến ung thư viêm gan B.
+ Gene P → Viral DNA polymerase.

● Function with DNA Polymerase:

○ R dependent polymerase, DNAdependent polymerase, RNase H activities.
○ Executes multi-fun required for life cycle: Viral RNA binding, RNA packaging,
protein priming, template switching, DNA synthesis, and RNA degradation.

Definition
HBsAg - The complex antigenic determinants
on all types of particles.
- It was formerly designated Australia
Ag or hepatitis associated antigen
(HAA)
- 3 sizes: S, M, L.

HBcAg - Only found in Dane particles (with the

2 nm core of HBV).

HBeAg - Extracirculate antigen→ circulate as a

soluble protein.
- Related to the nucleocapsid of HBV.
⇒ escape out to the blood during viral
replication.

HBV Life Cycle

a. Internalized by endocytosis
b. Naked nucleocapsid heads to the nucle. us & genome into nucleus.
c. rcDNA → cccDNA by DNA polymerase.
d. transcription.
e. translation. → either go to make Dane particles (42nm) or other smaller particles (22nm).
f. pgRNA (pregenomic RNA) is encapsidated
g. pgRNA is reversely transcripted into rcDNA
h. Mature virion is secreted out.
i. OR come back to the nucleus.
j. Optional step: viral DNA could be integrated into host genome.
 ●
Notes:
-
Chưa biết receptor cụ thể của HBV.
Gắn vào TB ⇒ nucleocapsid giải phóng vào TB⇒ rcDNA into nucleus.
-
Cắt DNA polymerase khỏi sợi âm → cắt RNA primer trên sợi dương đi ⇒ tổng hợp
-
cccDNA.
- cccDNA đc transcripted thành 4 dạng mRNA như trên → pgRNA + preS1 + preS2 + X
- Các tiểu thể nhỏ (không có core) là tốt thí. Vùng precore code cho BeAg.
→ Đột biến ở vùng precore => dẹp E => thoát miễn dịch vì mình không nhận ra đc. E thì
không ảnh hưởng gì đến nhân lên=> nhân lên bth

● 3 ĐIỂM CỐT LÕI CỦA LIFE CYCLE (phải nhớ):

+ Reverse transcription: One of the mRNAs is replicated with a reverse transcriptase
making the DNA that will eventually be the core of the progeny virion.
+ RNA intermediate: HBV replicates through an RNA intermediate and produces and
release antigenic particles.
+ Integration: viral DNA will be integrated into host genome.

Clinical outcomes of HBV

- Cirrhosis and Hepatic carcinoma: only in chronic active hepatitis.

Clinical manifestation of Acute hepatitis:

● Sign and symptoms:
- Most people are asymptomatic, esp. children <5 yo.
- 30%-50% people age > 5 are symptomatic..
 - Signs and symptoms:
+ fever, fatigue.
+ abdominal pain, joint pain, loss of appetite, nausea, vomiting.
+ dark urine, pale (clay) stool, jaundice (yellow skin, sclera, mucus membrane). .
+ Prolonged prothrombin time.
● Stages:

Stage Duration Characteristics

Incubation stage 6w-6m • Clinical manifestations: age-dependents.

• Newborn: normally asymptomatic
• 1-5 yo: 5-15% have clinical manifestations
• Older children and adults: 10-30%
symptomatic.

• Symptoms: flu-like. Some have physical

signs: jaundice, dark urines, clay-colored
stool and hepatomegaly

Prodromal stage 1-2 weeks • Malaise, fever <39.5oC, fatigue, myalgia,

anorexia, nausea, vomiting.
→ May experience weight loss, right-
upperquadrant pain with hepatomegaly.

Icteric phase 1m • Dark urine + jaundice.

• Extrahepatic manifestations: virus-specific
immune complex injury (acute necrotizing
vasculitis polyarteritis nodosa) and
membranous glomerulonephritis.

• Diagnosis is based on liver enzymes, viral

Ag, Ab, and nucleic acid.
• Total bilirubin is increased but normally
<10mg/dL, prolongation of prothrombin time.

• Pathologic features: lobular disarray.

• May lead to fulminant hepatitis

Post Icteric phase • Recovery

• Reactivation
• Chronic progression

Chronic Hepatitis B
What - HBsAg is positive for more than 6 months.
 Characteristics - Highest mortality rate.
- More common in infant, apx. 90% infected infants obtain
chronic carrier.

Symptom • May have some elevation of liver enzymes.

• HBV virions, HBV DNA: detected in blood (active viral

replication)

• Pathological features: active inflammation with hepato cellular

necrosis and may be fibrosis.

Vaccination - Vaccination is available and is recommended for children

as part of the standard vaccination schedule and for adults
at greater risk (e.g., those with certain diseases,
intravenous drug users, and those who have sex with
multiple partners)
- Health-care agencies are required to offer the HBV
vaccine to all workers who have occupational exposure to
blood and/or other infectious materials.

Liver cirrhosis - Final outcome of active chronic hepatitis. Fibrosis is the

precursor.
- Mostly caused by HSC - hepatic stellate cell (aka Ito
cell).
- Many other types of cells, cytokines and miRNAs are
involved:
• Defenestration and capillarization of liver sinusoidal
endothelial cells are major contributing factors to hepatic
dysfunction in liver cirrhosis.

• Activated Kupffer cells destroy hepatocytes and

stimulate the activation of HSCs.

• Repeated cycles of apoptosis and regeneration of

hepatocytes contribute to pathogenesis of cirrhosis.

• At molecular level, many cytokines are involved in

mediation of signaling pathways that regulate activation of
HSCs and fibrogenesis.

X-protein and HCC

- X protein (HBx) is associated with HCC - hepatocellular carcinoma.
- HBx will affect: inhibit DNA repair, regulation of gene expression and activation of some
signaling pathways.

HBV epidemiology
 - ⅓ of the world population has been infected.
- 15-25% of these die to liver-related disease.

Transmission
- Mean incubation period: 120 Days.
Horizontal transmission Perinatal transmission

-Human-to-human. - Can cross placenta.

-Infectious Blood, Body fluid (semen or - 90% of infected infants becomes
saliva), Mucosal contact & Sexual chronically.
contact.
Ex: contaminated needles, sexual contact,
healthcare worker, blood transfusion.
- NOT via casual contact (kissing,
shaking hand) or breastfeeding.

Population at risk
- HIGHEST risk for people who do IV drug and sexual contact.

Why HBV testing is important?

• Not infected with HBV → vaccination and non-specific prevention
• Already infected with HBV → Health-care
• Treatment decision & follow-up
• Antiviral resistance follow-up
• Molecular epidemiology (genotype)
• Sex partner(s) or companies: identify what to do to protect the health

Who should be screened for HBV? → high risk people

- People borned in high rate regions.
- Men-men sex.
- IV drug user
- HIV people and immunosuppressive patients.
- People with close contact with chronic hepatitis patients.
- People with end-stage renal disease (hemodialysis).
 - Blood and tissue donor.
- People with elevated liver enzyme.
- Pregnant women. → should only test for HBsAg.
- Infants borned to infected mother.

Testing indication
1. Serological testing: antigen and antibody.
2. Molecular testing: RT-PCR, genotyping, sequencing for resistance detection.

Interpretation
- Chỉ cần học 5 case này:

Notes: Cứ có HBsAg (+), HBcAb thì nhắm mắt mà nói bị nhiễm HBV TỰ NHIÊN, chưa cần biết
acute hay chronic. -> IgM (+) là yếu tố marker để phân biệt mạn và cấp. (2 markers của nhiễm
tự nhiên). Cứ là viêm gan là có 2 cái này. HBsAg chỉ âm khi hồi phục. IgM là marker để phân
biệt mãn tính và cấp tính.
Tiêm vaccine vào thì HBsAg LUÔN ÂM tính. Vì nó không nhân lên đc và nồng độ quá thấp.
(Không baog có dược động học của vaccine)
PHẢI BIẾT:
Cảm nhiễm: cả 6 đều âm tính.
Vaccine: mỗi HBsAb dương tính.
Phân biệt cấp-mạn, vaccine và tự nhiên.

Precore mutation
- Possible mutations of hepatitis virus genome:
• Hepatitis B Surface Antigen Mutants.
• Mutations in the Precore, Basal Core Promoter, and Core Genes
• Hepatitis B Virus DNA Polymerase Mutants

Histopathology

● Lesions for all types of hepatitis is similar:

• Panlobular infiltration with mononuclear cells, hepatic cell necrosis, hyperplasia of
Kupffer cells, and variable degrees of cholestasis.
• Hepatic cell regeneration is present, as evidenced by numerous mitotic figures,
multinucleated cells, and “rosette” or “pseudoacinar” formation
• Necrosis: ballooning of cells → Councilman body (shrink and become acidophilic).
• Chronic - exclusive: Large hepatocytes with a ground-glass inclusion of the cytoplasm → these
cells contain HBsAg and can be identified histochemically with orcein or aldehyde fuchsin

Pathology
- How hepatitis B causes disease?
- HBV infected cell → attacked by cytolytic T cell ⇒ necrosis of hepatocytes.
⇒ People with defects in cellular immune response will more likely to remain chronically
infected.
- Cytolytic T cell would be invited by Nucleocapsid protein (HBcAg and HBeAg)
displayed on host cell.
- Difference in CD8+ cytolytic T cell response and the spread of antiviral cytokine ⇒ lead
to different outcomes.
- More severe disease.
Disease Characteristics

Concomitant HDV and HBV (“BuDdy”) → More severely liver injury.

Newly transplanted liver yet infected. • Liver transplant patients for end-stage
chronic hepatitis B

• Occasional, rapidly progressive liver injury

appears in the new liver

→ Fibrosing cholestatic hepatitis (FCH)

and choking of the cell with overwhelming
HBsAg.
 • Despite the influence of immunosuppressive
agents required to prevent allograft rejection,
HBV can still have a direct cytopathic effect
on liver cells, independent of the immune
system

Neonatal period infection - Weak immune response =

immunologic tolerance for HBV.
→ Absence of acute hepatitis period
⇒ straight to chronic, often life-long infection.
(90%)
- After decades, become liver cirrhosis and
hepatocellular carcinoma. (HCC) →
death.

Adolescence or early adulthood - Super strong immune reaction ⇒ Always

have acute hepatitis as a rule.

Adulthood - Low chance of chronicity → Low chance

of HCC.

Extrahepatic manifestation of HBV infection

Reason Tissue damages caused by immune complexes is the cause. (HbsAg -

Antibody)

Manifestation The occasional prodromal serum sickness in acute hepB

→ Caused by the deposition of HBsAg-anti-HBs circulating immune complexes in

the blood vessels (small and medium size) ⇒ leading to activation of the
complement system and depressed serum complement levels.

Glomerulonephritis & nephritic syndrome

→ HBsAg, immunoglobulin, and C3 deposition in glomerular basement
membrane.

Polyarteritis nodosa
(<1% chronic patient have this)
→ 20% to 30% of patients have HBsAg in serum

Essential mixed cryoglobulinemia (EMC)

→ Characterized clinically by arthritis, cutaneous vasculitis (palpable
purpura), and occasionally glomerulonephritis, and serologically by the
presence of circulating cryoprecipitate immune complexes

Treatment
- Target: HBV DNA Polymerase ( for all Currently available oral drugs)
 - Treatment goal: Reduce HBV DNA to super low that RT-PCR cannot detect.
- Ensure a degree of virologic suppression that will allow biochemical remission, histologic
improvement, and prevention of complications.

Therapy for chronic HBV → ANTIVIRALS

Only recommended for patient with active chronic hepatitis who have high risks of
progression in the short-term.

Interferon-a (IFNa) & • Direct antiviral effect, suppressing HBV replication

pegylated IFNa.
• Major effect: immunologic such as inducing and/or facilitating
a hepatic flare that resolves the infection and establishes
immunologic control that prevents virus rebound

Nucleoside(tide) analogs → as RT inhibitor - inhibit viral DNA polymerase.

(NUCs) • Stop HBV replication

Therapy for end-stage patient

Recommend NUC → control of viral replication, accompanied by significantly

improved liver functions.

NOT IFNa • Not recommended IFN because it increases the risk of liver
failure due to immune killing of the remaining functional
hepatocytes.

• Not recommended IFN for recipients of liver transplantation

because of the risk of inducing liver graft rejection.

Vaccine
● For chronic HBV → use HBx-based vaccine.
● pre-S1-based.
● Therapy of liver fibrosis and cirrhosis:
• Therapies to eliminate the etiological factors
• Anti-inflammatory and immunosuppressive therapies
• Suppressing activation and promoting apoptosis of HSCs
• Protect liver function and promote hepatocyte regeneration
• Gene therapy and targeted therapy
• Complementary and alternative medicine

Hepatitis D virus
● Only occur in HBV-infected patient. Because HBV provides HBsAg, which is required for the
replication of HDV. ⇒ HBV vaccination also prevents HCV infection
● Genome characteristics:
• Single stranded, self complementary RNA, encapsidated in HBsAg
• Small, amorphous particle
• RNA encodes one protein: delta antigen ⇒ required for replication.
• Replicates via RNA directed RNA synthesis, catalyzed by host RNA
polymerase II.
● Co-infection or superinfection with HBV:
○
○ Cons: more severe acute disease and a higher risk of fulminant hepatitis.
○ Pros: chronic HBV infection is less frequently in HBV-HDV co-infection patients.
○ BUT: if already have chronic HBV, superinfection with HDV would be more prone
to chronic HDV and
○ Superinfection more rapid & severe than co-infection.