Hepatitis C
Hepatitis C is likely to become a significant public health problem in the UK in
the next decade. It is thought around 200,000 people are chronically infected with
the virus. At risk groups include intravenous drug users and patients who received
a blood transfusion prior to 1991 (e.g. haemophiliacs).
Pathophysiology
* hepatitis C is a RNA flavivirus
* incubation period: 6-9 weeks
Transmission
* the risk of transmission during a needle stick injury is about 2%
* the vertical transmission rate from mother to child is about 6%. The risk is
higher if there is coexistent HIV
* breastfeeding is not contraindicated in mothers with hepatitis C
* the risk of transmitting the virus during sexual intercourse is probably less
than 5%
* there is no vaccine for hepatitis C
After exposure to the hepatitis C virus only around 30% of patients will develop
features such as:
* a transient rise in serum aminotransferases / jaundice
* fatigue
* arthralgia
Investigations
* HCV RNA is the investigation of choice to diagnose acute infection
* whilst patients will eventually develop anti-HCV antibodies it should be
remembered that patients who spontaneously clear the virus will continue to have
anti-HCV antibodies
Outcome
* around 15-45% of patients will clear the virus after an acute infection
(depending on their age and underlying health) and hence the majority (55-85%) will
develop chronic hepatitis C
Chronic hepatitis C
Chronic hepatitis C may be defined as the persistence of HCV RNA in the blood for 6
months.
Potential complications of chronic hepatitis C
* rheumatological problems: arthralgia, arthritis
* eye problems: Sjogren's syndrome
* cirrhosis (5-20% of those with chronic disease)
* hepatocellular cancer
* cryoglobulinaemia: typically type II (mixed monoclonal and polyclonal)
,* porphyria cutanea tarda (PCT): it is increasingly recognised that PCT may develop
in patients with hepatitis C, especially if there are other factors such as alcohol
abuse
* membranoproliferative glomerulonephritis
Management of chronic infection
* treatment depends on the viral genotype - this should be tested prior to
treatment
* the management of hepatitis C has advanced rapidly in recent years resulting in
clearance rates of around 95%. Interferon based treatments are no longer
recommended
* HCV RNA (viral load) is used to monitor response to treatment
* the aim of treatment is sustained virological response (SVR), defined as
undetectable serum HCV RNA six months after the end of therapy
* currently a combination of protease inhibitors (e.g. daclatasvir + sofosbuvir or
sofosbuvir + simeprevir) with or without ribavirin are used
Complications of treatment
* ribavirin - side-effects: haemolytic anaemia, cough. Women should not become
pregnant within 6 months of stopping ribavirin as it is teratogenic
* interferon alpha - side-effects: flu-like symptoms, depression, fatigue,
leukopenia, thrombocytopenia
Exotoxins and endotoxins
Exotoxins are secreted by bacteria where as endotoxins are only released following
lysis of the cell. Exotoxins are generally released by Gram positive bacteria with
the notable exceptions of Vibrio cholerae and some strains of E. coli
It is possible to classify exotoxins by their primary effects:
* pyrogenic toxins
* enterotoxins
* neurotoxins
* tissue invasive toxins
* miscellaneous toxins
Pyrogenic toxins
,Pyrogenic toxins stimulate the release of endogenous cytokines resulting in fever,
rash etc. They are superantigens which bridge the MHC class II protein on antigen-
presenting cells with the T cell receptor on the surface of T cells resulting in
massive cytokine release.
Organism
Toxin
Notes
Staphylococcus aureus
Toxic shock syndrome (TSST-1 superantigen) toxin
Results in high fever, hypotension, exfoliative rash
Streptococcus pyogenes
Streptococcal pyrogenic exotoxin A & C
Results in scarlet fever
Enterotoxins
Enterotoxins act on the gastrointestinal tract causing one of two patterns of
illness:
* diarrhoeal illness
* vomiting illness ('food poisoning')
Organism
Toxin
Notes
Vibrio cholerae
Cholera toxin
Causes activation of adenylate cyclase (via Gs) leading to increases in cAMP
levels, which in turn leads to increased chloride secretion and reduced sodium
absorption
Shigella dysenteriae
Shiga toxin
Inactivates 60S ribosome → epithelial cell death
Escherichia coli
1. Heat labile toxin
2. Heat stabile toxin
1. Activates adenylate cyclase (via Gs), increasing cAMP → watery diarrhoea
2. Activates guanylate cyclase, increasing cGMP → watery diarrhoea
Staphylococcus aureus
Staphylococcus aureus enterotoxin
Vomiting and diarrhoeal illness lasting < 24 hours
Bacillus cereus
Cereulide
Potent cytotoxin that destroys mitochondria. Causes a vomiting illness which
may present within 4 hours of ingestion
, Neurotoxins
Neurotoxins act on the nerves (tetanus) or the neuromuscular junction (botulism)
causing paralysis.
Organism
Toxin
Notes
Clostridium tetani
Tetanospasmin
Blocks the release of the inhibitory neurotransmitters GABA and glycine
resulting in continuous motor neuron activity → continuous muscle contraction →
lockjaw and respiratory paralysis
Clostridium botulinum
Botulinum toxin
Blocks acetylcholine (ACh) release leading to flaccid paralysis
Tissue invasive toxins
Organism
Toxin
Notes
Clostridium perfringens
α-toxin, a lecithinase
Causes gas gangrene (myonecrosis) and haemolysis
Staphylococcus aureus
Exfoliatin
Staphylococcal scalded skin syndrome
Miscellaneous toxins
Organism
Toxin
Notes
Corynebacterium diphtheriae
Diphtheria toxin
ADP ribosylates elogation factor (EF-2), resulting in inhibition, causing a
'diphtheric membrane' on tonsils caused by necrotic mucosal cells. Systemic
distribution may produce necrosis of myocardial, neural and renal tissue
Pseudomonas aeruginosa
Exotoxin A
Hepatitis C is likely to become a significant public health problem in the UK in
the next decade. It is thought around 200,000 people are chronically infected with
the virus. At risk groups include intravenous drug users and patients who received
a blood transfusion prior to 1991 (e.g. haemophiliacs).
Pathophysiology
* hepatitis C is a RNA flavivirus
* incubation period: 6-9 weeks
Transmission
* the risk of transmission during a needle stick injury is about 2%
* the vertical transmission rate from mother to child is about 6%. The risk is
higher if there is coexistent HIV
* breastfeeding is not contraindicated in mothers with hepatitis C
* the risk of transmitting the virus during sexual intercourse is probably less
than 5%
* there is no vaccine for hepatitis C
After exposure to the hepatitis C virus only around 30% of patients will develop
features such as:
* a transient rise in serum aminotransferases / jaundice
* fatigue
* arthralgia
Investigations
* HCV RNA is the investigation of choice to diagnose acute infection
* whilst patients will eventually develop anti-HCV antibodies it should be
remembered that patients who spontaneously clear the virus will continue to have
anti-HCV antibodies
Outcome
* around 15-45% of patients will clear the virus after an acute infection
(depending on their age and underlying health) and hence the majority (55-85%) will
develop chronic hepatitis C
Chronic hepatitis C
Chronic hepatitis C may be defined as the persistence of HCV RNA in the blood for 6
months.
Potential complications of chronic hepatitis C
* rheumatological problems: arthralgia, arthritis
* eye problems: Sjogren's syndrome
* cirrhosis (5-20% of those with chronic disease)
* hepatocellular cancer
* cryoglobulinaemia: typically type II (mixed monoclonal and polyclonal)
,* porphyria cutanea tarda (PCT): it is increasingly recognised that PCT may develop
in patients with hepatitis C, especially if there are other factors such as alcohol
abuse
* membranoproliferative glomerulonephritis
Management of chronic infection
* treatment depends on the viral genotype - this should be tested prior to
treatment
* the management of hepatitis C has advanced rapidly in recent years resulting in
clearance rates of around 95%. Interferon based treatments are no longer
recommended
* HCV RNA (viral load) is used to monitor response to treatment
* the aim of treatment is sustained virological response (SVR), defined as
undetectable serum HCV RNA six months after the end of therapy
* currently a combination of protease inhibitors (e.g. daclatasvir + sofosbuvir or
sofosbuvir + simeprevir) with or without ribavirin are used
Complications of treatment
* ribavirin - side-effects: haemolytic anaemia, cough. Women should not become
pregnant within 6 months of stopping ribavirin as it is teratogenic
* interferon alpha - side-effects: flu-like symptoms, depression, fatigue,
leukopenia, thrombocytopenia
Exotoxins and endotoxins
Exotoxins are secreted by bacteria where as endotoxins are only released following
lysis of the cell. Exotoxins are generally released by Gram positive bacteria with
the notable exceptions of Vibrio cholerae and some strains of E. coli
It is possible to classify exotoxins by their primary effects:
* pyrogenic toxins
* enterotoxins
* neurotoxins
* tissue invasive toxins
* miscellaneous toxins
Pyrogenic toxins
,Pyrogenic toxins stimulate the release of endogenous cytokines resulting in fever,
rash etc. They are superantigens which bridge the MHC class II protein on antigen-
presenting cells with the T cell receptor on the surface of T cells resulting in
massive cytokine release.
Organism
Toxin
Notes
Staphylococcus aureus
Toxic shock syndrome (TSST-1 superantigen) toxin
Results in high fever, hypotension, exfoliative rash
Streptococcus pyogenes
Streptococcal pyrogenic exotoxin A & C
Results in scarlet fever
Enterotoxins
Enterotoxins act on the gastrointestinal tract causing one of two patterns of
illness:
* diarrhoeal illness
* vomiting illness ('food poisoning')
Organism
Toxin
Notes
Vibrio cholerae
Cholera toxin
Causes activation of adenylate cyclase (via Gs) leading to increases in cAMP
levels, which in turn leads to increased chloride secretion and reduced sodium
absorption
Shigella dysenteriae
Shiga toxin
Inactivates 60S ribosome → epithelial cell death
Escherichia coli
1. Heat labile toxin
2. Heat stabile toxin
1. Activates adenylate cyclase (via Gs), increasing cAMP → watery diarrhoea
2. Activates guanylate cyclase, increasing cGMP → watery diarrhoea
Staphylococcus aureus
Staphylococcus aureus enterotoxin
Vomiting and diarrhoeal illness lasting < 24 hours
Bacillus cereus
Cereulide
Potent cytotoxin that destroys mitochondria. Causes a vomiting illness which
may present within 4 hours of ingestion
, Neurotoxins
Neurotoxins act on the nerves (tetanus) or the neuromuscular junction (botulism)
causing paralysis.
Organism
Toxin
Notes
Clostridium tetani
Tetanospasmin
Blocks the release of the inhibitory neurotransmitters GABA and glycine
resulting in continuous motor neuron activity → continuous muscle contraction →
lockjaw and respiratory paralysis
Clostridium botulinum
Botulinum toxin
Blocks acetylcholine (ACh) release leading to flaccid paralysis
Tissue invasive toxins
Organism
Toxin
Notes
Clostridium perfringens
α-toxin, a lecithinase
Causes gas gangrene (myonecrosis) and haemolysis
Staphylococcus aureus
Exfoliatin
Staphylococcal scalded skin syndrome
Miscellaneous toxins
Organism
Toxin
Notes
Corynebacterium diphtheriae
Diphtheria toxin
ADP ribosylates elogation factor (EF-2), resulting in inhibition, causing a
'diphtheric membrane' on tonsils caused by necrotic mucosal cells. Systemic
distribution may produce necrosis of myocardial, neural and renal tissue
Pseudomonas aeruginosa
Exotoxin A
