acute hepatitis
swollen hepatocytes, small areas of necrosis
chronic hepatitis
graded ac cording to degree of inflammation, necrosis, fibrosis
cirrhosis
reduced hepatocyte mass
fibrosis
nodules of regenerating hepatocytes surrounded by fibrosis
derangement of flow from portal veins to hepatic vein (shunting)
impaired function - filtering of blood from GIT; protein production
LFTs
liver function tests
liver enzyme tests
ALT
AST
ALP
gammaGT
hepatocyte damage indicative liver enzymes
ALT, AST
synthetic function indicative tests
albumin
total protein
prothrombin time
excretory function indicative tests
bilirubin
true tests of liver function testst
albuin
total protein
prothrombin time
bilirubin
ALT
alanine aminotransferase
found within hepatocyte cytoplasm
AST
aspartate aminotransferase
found within hepatocyte cytoplasm (but also in heart, muscle, intestine, pancreas
presence of these 2 in serum indicates cellular damage
ALT and AST
ALP
alkalike phosphatase
found within cells lining biliary system (but also in bone, intestine, placenta)
increased synthesis in cholestasis
gammaGT
gamma glutamyl transferase
found within cells lining biliary system
raised in cholestasis
bilirubin
the laboratory measures conjugated and total bilirubin in the blood
in viral hepatitis, elevated bilirubin may be conjugated, or conjugated + unconjugated
albumin, total protein
produced by the liver
decreased levels in chronic liver (or other) disease
prothrombin time
increased
reduced synthesis of clotting factors
conjugation of bilirubin in the liver
unconjugated bilirubin enters the sinusoids and is taken up by the hepatocytes, where it is conjugated and excreted through the bile ductile
cause of elevated bilirubin in viral hepatitis
damaged hepatocytes result in conjugated and unconjugated bilirubin, and liver enzymes, entering the sinusoids and into the circulation
liver function test abnormalities fall into two categories
cholestasis and hepatocellular damage
both patterns commonly present together
cholestasis
interrupted bile flow between hepatocyte and GIT
cause can be intrahepatic and extrahepatic
signs of cholestasis
increased bilirubin and majority is conjugated
increased ALP - suggests liver but may come from other tissues
increased ALP and increased gammaGT - both together indicated liver origin
increased gammaGT - alone suggests alcohol excess
ALT/AST - normal or mildly elevated
increased ALP and gammaGT in chelastasis
both at the same time suggests liver origin
increased gammaGT alone in cholestasis indicates
alcohol excess
hepatocellular damage
enzymes (ALT and AST) are released from damaged cells
hepatocellular damage signs
increased ALT
increased AST
increased bilirubin and majority is conjugated
> 10x normal degree of increased AST in hepatocellular damage
acute severe insult
- viral hepatitis
- toxic drugs - paracetamol
- hypoxia
<5x normal increased AST in hepatocellular damage
other infections
alcohol
some medications
hep B and C both cause
chronic infection
serious sequelae - cirrhosis, HCC
hep B
DNA virus with double stranded circular genome
a number of components of the virus are antigenic
these, and the host antibodies wot which they give rise, form the basis of the routinely used laboritory tests for infection with this virus
HBsAg
hep B surface antigen
found on intact visions or in the form of filamentous or spherical particles
antigen and antibody both detectable in serum
HBcAg
Hep B core antigen
present in the liver but not detected in blood
not detected in blood
only resulting antibody is detectable in serum
HBeAg
hepatitis B e antigen
a soluble cleavage product of the core structural polypeptide
both antigen and resulting antibody and detectable in serum
HBV DNA
hep B DNA
can be detected in serum using PCR tests
HBV DNA and HBV viral load (if quantified)
serological response to acute infection
70% develop subclinical or antiicteric hepatitis
30% develop icteric hepatitis
HBsAg appears during the incubation period, 4 weeks before evidence of hepatitis (jaundice or elevated liver enzymes)
patients with HBsAg are
infective
if HBsAg is present for 7 weeks or less
the patient is unlikely to develop clinically evident hepatitis
the appearance of HBeAg roughly correlates with
HBsAg
correlates with viral replication and indicates high infectivity
testing for HBeAg in acute infection
does not usually offer useful information
it’s presence has more significance in persistent infection
HBcAb is detectable
before the onset of liver damage and persists for years
only detectable through natural infection - does not arise from vaccination
indicator of recent infection with Hep B
HBcAb IgM
persists for 4 months
HBeAb in acute infection
shortly after HbeAg disappears, HBaAb appears
persists for a couple of years after resolution of acute infection
HBsAb in acute infection
doesn’t appear immediately after the disappearance of HBsAg
delay of several months before it appears and then persists for years
HBsAb is a protective antibody and neutralises the virus
protective antibody that neutralises the virus
HBsAb
antibody that may arise from natural infection or from vaccination
HBsAb
HBV DNA detectable by
30 days following acute infection
can be detected 21 days before HBsAg appears in serum
if infected with HBV as a neonate
almost all cases will remain chronically infected
persistence of HBsAg in the serum for 6 months or ore
defines chronic infection
or the ‘carrier’ state
HBcAb in chronically infected patients
develops and persists as it does in those with acute self limiting infection
HBsAb in persistent infection
does not arise in chronically infected patients
HBeAg in chronic patients
arises as it does in acute self limiting infection
correlated with HBsAg
may or may not be replaced with HBeAb
mutant viruses not producing HBeAg
mostly pre-core mutants
don’t produce HBeAg at all
core and pre core gene regions
HBcAg and HBeAg are a product of a single gene region consisting of the pre-core and core regions
these are two initiation codons, one in the pre-core region and one in the core region
how HBeAg and HBcAg are made
when translation starts at the pre-core initiation codon, the resulting polypeptide has its ends cleaved off in the host cells endoplasmic reticulum resulting in HBeAg
when translation starts at the core initiation codon, the resulting polypeptide is HBcAg
pre core mutant
production of a stop codon in the precode region of the genome
viral mutants cannot produce HBeAg
hosts infected with pre core mutants will not have this marker of viral replication and high infectivity in their serum
pre core mutants still produce
HBcAg
pre core mutants cannot produce
HBeAg
mutation in pre core mutants
stop codon in the pre-core region of the genome
4 stages of chronic hep B infection
- immune tolerant
- immune clearance
- immune control
- immune escape
- immune tolerant stage features
seen in those who acquired infection as neonates
persists for 20-30 years
minimal liver damage
low risk of progression
immune tolerant stage laboratory
positive HBeAg
high viral load
- immune clearance features
active, cytotoxic immune response resulting in liver damage, fibrosis
- immune clearance stage laboratory
HBeAg eventually becomes HeAb
high viral load falls to low levels
ALT elevated but fluctuates
- immune control features
inactive carriers
minimal liver inflammation
low risk of complications
small % flare up and develop complications
- immune control lab
negative HBeAg
low viral load
ALT normal
- immune escape features
virus mutates and no longer produces HBeAg (usually pre core mutant)
can still replicate and get selected
inflammation, significant fibrosis
high incidence of complications
- immune escape lab
negative HBeAg
low viral load
ALT elevated but fluctuates
Hep C virus symptomatic illness
occurs in only 15-30% of cases
Hep C virus incubation time
5-12 weeks
if HCV RNA still detected at 6 months
chronic infection
HCV antibody persists
regardless of whether infection is cleared
ALT levels HCV
fluctuate throughout course of infection
lab diagnosis of Hep A
IgM anti-HAV indicates recent infection, but may persist for up to 12 months
IgG anti-HAV provides evidence of recent or previous infection or immunisation
lab diagnosis of Hep E
IgG anti-HEV provides evidence of recent or previous infection specific IgM testing not available locally
samples with positive IgG will get HEV PCR testing
laboratory diagnosis of Hep D
IgG anti-HDV available locally
will only be performed if HBsAg is also present