Hepatitis B Virus infection

Ermias D. (MD)

History

Krugman et al (1967) – serum hepatitis/ HB

Blumberg – Au Ag; (1976 Noble winner) Prince – SH Ag

… HBsAgOpened up for rigorous investigations

Ethiopian epidemiology E Tsega – serologic survey in 500 individuals from 5 regions

6.2% HBsAg, 42% overall viral markers, increasing pattern anti HBe and decreasing HBeAg with age 3 individuals with delta Ab

Arsi region among 20-24 yrs – 80% H. Kefenie – among AA hospital personnel's (432)

HBsAg 9.02% antiHBs 46.25% antiHBc 73.6% at least one marker 76.38%

A. Abebe - seroepidemiology in AA HBsAg 7% HBeAg 23% increasing with age any marker 70% (40-49yrs)

Gondar 14.4% --- 8.2% (blood donors) Review article (E. Tsega) - HBsAg 8-12%, over all markers 70 -79%

virology

Hepadnaviridae – hepatotrophic DNA virus Small amount in kidney, pancreas,

mononuclear cells Infected cells produce two distinct subviral

lipoproteins – HBsAg (spheres and filamentous forms)

Viral structure

40-42nm

Outer lipoprotein Envelope

(3 Surface Ag,glycoprotein)

Core, viral genomeDNA 3.2kb

polymerase

8 subtypes group reactive and subtype Ag – a, d or y, w or r

Genes and proteins preS-S gene

S - Major (HBsAg), preS2 – middle (M), PreS1 - large (L) – binding, assembly, release

preC-C HBcAg – target of immune response HBeAg – marker of active replication

P region – viral polymerase – DNA synthesis, RNA encapsidation

X gene – gene expression, vivo replication, spread

Viral replication cycle Fusion Core presentation to cytosol – - then nucleus DNA – cccDNA RNA transcription (host RNA polymerase II) Pass to cytoplasm Translation of envelop, core, polymerase, x, preC Assembly (including single RNA) Sequential DNA synthesis (first from RNA by RT,

the second from the first synthesized DNA) Recycle from the cytoplasm with in the cell itself or

bud out and infect other cells

pathogenesis Viral replication – not cytotoxic

Many carriers - asymptomatic Host immune response – hepatocellular injury

Pt with immune defects – minimal injury In acute self limited disease – strong T cell response

– MHC II CD4 T, MHC I CD8 T Cytotoxic T response against - core, polymerase, envelope

proteins (central roll in viral clearance) Helper T against – C and P proteins

Chronic infection – attenuated T cell response Virogous Ab response

Conti… Transgenic mice - tolerant to HBV proteins and there

is no significant liver injury Administration of cytotoxic T cell from syngeneic

animals – acute liver injury Few hepatocytes are directly killed by the cyt. T cell

and their target Secondary antigen nonspecific inflammatory

responses, cytotoxic by products of inflammatory response, TNF, free radicals proteases, other immune cells

TNF and IFN have antiviral effect with out killing target cells – important for viral clearance

Cytokine release by un related hepatic infections has similar effect

Natural history Primary infection is mostly asymptomatic Mostly self limiting with viral clearance and

lasting immunity 5% persistent infection – viral replication and

viremia continues Persistent infection:

Symptomatic (chronic) – abnormal liver function and histology

Asymptomatic (carriers) – normal serum amino transferase and histology

20% chronic – fibrosis and regenerative nodules (cirrhosis)

Viral DNA HBsAg HBeAg Anti HBc ALT AntiHBe AntiHBs

Viral DNA HBsAg Anti HBc HBeAg ALT

AntiHBe ALT

Hepatocellular carcinoma 100 times risk in chronically infected patients HBsAg and HBeAg positive have higher risk Even anti HBe antibody carriers have risk Molecular mechanism incompletely

understood Twice a year screening with serum α FP or

liver sonography or both α-FP low positive predictive value (9-30)

Hepatitis D Defective RNA virus

Requires host polymerase II for replication Require the helper function of HBV to cause liver injury

Endemic in HB infected Duration of infection cannot out last HBV infection

Transmission – close personal, percutaneous Simultaneous co infection

Chronic infection – <5%, fulminant failure 1%, mostly complete recovery

Super infection in HBsAg positives – fulminant failure 5% 80-90% chronic infection and rapid cirrhosis and HCC

Manifestation Similar to other viral hepatitis

IP 4-12 weeks Prodromal symptoms – acute viral infection (1-2 wks) Clinical Jaundice, nausea, vomiting, alteration in

olifaction and taste. Dark urine, clay like stool Icterus, fever, RUQ tenderness Recovery phase liver enlargement and functional

abnormality may persist (2-12 wks)

In HDV infection - 90% asymptomatic, similar sx HDV Ag 20%, HDV RNA 90% elevated transaminases

Extrahepatic manifestations

Immune complex mediated Serum sickness like syndrome (acute HB) Glomerulonephritis (hypocomplementemic) with

nephritic syndrome Polyarteritis nodosa Essential mixed cryoglobulinemia (HCV) Pulmonary hemorrhage, vasculitis Acute pericarditis, polyserositis Henoch-Schonlein purpura

Diagnosis

Case discussion

38 yrs old male Bilateral leg swelling for 5 years

History Bilateral leg swelling since 4 wks following an acute episode of

diarrheal disease The diarrhea was watery moderate in amount and subsided after four

days, pt took norfloxacillin He has the leg swelling for the last five yrs waxing and wanning in

intensity Gets worse with stressful situations, hot whether, and anorexia (poor

feeding) Long standing dyspeptic sx – take anti acids, PPI, H2B Infrequent use of paracitamol, diclofenac for migraine Bowel habit is often constant with once per day, no stool color changes 2 pack yrs of smoking before 10 yrs Nutritional hx - 3meals/day small; No cardiac sx or illness before No urinary abnormality

p/E

V/s in the normal ranges Wt 55kg

Pedal and pretibial gross pitting edema

Lab data

14/11/01 Hgb 17.5 Total serum protien – 6 (LLN 6.2) Alb - ?? Electrophoresis a/g 1.42 (normal) UA, liver enzymes, renal function, FBS,

abdominal US --- normal

Dec. 2004

Hgb – 17.1 ESR – 0 TFT – wnl Doppler of the leg vessels – normal ANA positive, LE body negative Cl- 118

Abdominal US, UA, liver enzymes, RFT, Na, K - wnl

Wbc 8700 L% 11 Hgb – 19.3 MCV – 87 UA protein +, repeat – negative for protein TSP 3.4, albumin 3.1 a/g – 1.31 (1.39 – 2.23)

ESR – 3 Cl- 117, CO2 13 (21-32) Lipid profile, liver enzymes, PT, Na, K, RFT, - WNL Stool 3X negative H.pylori serology - Negative

discussion

Protein lossing enteropathy Underlying cause ?? PUD

Long standing dyspepsia Polycythemia Elevated serum Cl- Low total protein and albumin