Download Micro Chapter 43 [4-20

Micro Chapter 43: Viral Hepatitis
Viral hepatitis – infection by viruses with a strong tropism for the liver, and like to replicate in
hepatocytes
The liver is the largest organ in the body, so it’s a major site for virus replication
85% of the liver is hepatocytes, the main epithelial cell in the liver, and target of most hepatitis viruses
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Jobs of hepatocytes:
o Making of plasma proteins – like albumin and clotting factors
o Glucose and lipid metabolism
o Metabolism and detoxification of xenobiotics, toxins, and drugs
o Conjugation and excretion of bilirubin – a breakdown product of heme
The liver is also home to many cells of the immune system – like interferons (innate) and antibodies
(adaptive)
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Kupffer cells – liver specific macrophage, that are important mediators of inflammatory
responses, especially cytokine release
The liver also has lots of kinds of T cells, especially natural killer T cells (NK cells)
o NK cells are part of innate immunity, and can make lots of cytokines
When the liver is damaged by viral infection, its normal functions are impaired, causing the symptoms
characteristic of viral hepatitis:
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Fever, abdominal pain, nausea, and vomiting are common in mild cases of viral hepatitis
More extensive liver damage can cause bilirubin to accumulate in the skin, leading to yellow
colored skin (jaundice)
In more severe cases, mental function is impaired due to failure to detox ammonia and toxins
absorbed from the GI tract, and bleeding can happen from decreased making of clotting factors
Lab tests in viral hepatitis will show elevated serum bilirubin and transaminases
o Transaminases – released from damaged hepatocytes
There are two ways the different hepatitis viruses will infect humans:
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Oral ingestion – done by HAV and HEV
o They go to the intestine, and then make their home in the liver, where they replicate
o Virus is shed into the bile ducts and returned to the intestine, where it can be excreted
in feces
o The feces can then contaminate food or drink – called fecal-oral spread
o With HAV and HEV, an immune response clears the liver and blood of the virus, and
causes lasting immunity to reinfection
o So HAV and HEV infection cause only a transient, self-limited infection
o Fatalities are rare, and most cases of HAV and HEV resolve
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Transient or persistent infection – done by HBV and HCV
o They first cause an acute infection that may or may not cause symptoms, but always
causes lots of replication of the virus in the liver
o The immune response to this is not always effective at clearing the infection
o So some people do clear acute infection, many don’t and progress to chronic infection
that is often lifelong
o Persistent infection is characterized by continued virus replication in the liver, and
release of infectious stuff into the blood
o Only a small % of HBV progresses to persistence in adults, while most HCV become
chronic
Page 439 – table 43-2 – modes of transmission of the hepatitis viruses
o HAV and HEV are the only fecal-oral transmissions
o All virus hepatitis can be spread parenteral, and through sexual contact
o Vertical transmission from mom to baby is done by HBV, HCV, and HDV (chronic ones)
What causes the liver damage in viral hepatitis:
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HBV and HCV virus replication in hepatocytes, does not directly injure the cell
o Instead, the host immune response makes TC cells against the viral antigens displayed by
MHC1s on the hepatocyte surface
o The Tc cells then kill the hepatocyte, and also release cytokines to cause more
inflammation and tissue injury
So the immune response in viral hepatitis gets rid of the infected cells and clears the infection,
but causes liver injury and causes the disease symptoms
A strong immune response can clear the primary infection, like in HAV or HEV infection, which
are always cleared in the primary infection
Host immune response can clear almost all HBV infections, but only 1/5 of primary HCV
infections
When the immune response isn’t enough to clear the primary infection, it becomes chronic
o Sometimes, the inadequate response continues to injure infected hepatocytes, causing
continuous liver damage – called chronic hepatitis
o Chronic hepatitis has symptoms similar to acute hepatitis, but they persist
o Not all persistent infections lead to liver damage though, and those who don’t are called
asymptomatic carriers
 They’re clinically fine, but are reservoirs to spread the infection
The liver responds to continuous damage from persistent infection, by regeneration, and sometimes
scarring (fibrosis)
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Extensive regeneration and fibrosis leads to cirrhosis, where nodules of regenerating
hepatocytes are accompanied by large bands of connective tissue
Cirrhosis usually indicates extensive loss of functioning liver cells, which may not regenerate,
leading to liver failure, which is fatal
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Chronic HCV infection is the leading need for liver transplants in the US
Also, decades of hepatocyte death and regeneration may cause liver cancer, due to mutations
o Chronic HBV and HCV greatly increase the risk for liver cancer
Hepatitis A virus (HAV)
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HAV is responsible for most cases of infectious hepatitis
HAV replicates A LOT in the liver, causing stool with tons of shed virus material
HAV is spread mainly through ingestion of fecally contaminated food or water
Once HAV gets into the intestines, it’s absorbed into the blood and goes through the portal
system to the liver
The HAV then infects the liver hepatocytes, and newly made virus stuff are released into the
bile ducts, and from there then excreted into feces
Also to a lesser extent, some virus gets out into the blood, causing a brief period where HAV can
be spread parentally or through blood transfusion
o HAV will hang out in the stool in much greater #’s, and for much longer, than in blood,
hence why most HAV is spread through fecal-oral route
Antibodies come neutralize the HAV, and are important in clearing the virus
Symptoms show up once the immune response kicks in, and IgM antibodies specific for HAV
show up
Symptoms are usually worse in adults than in kids
In highly endemic areas where there is poor sanitation, nearly all children become infected
with HAV in the first few years of life, but most stay asymptomatic
Adults from nonendemic areas who get HAV, are more likely to have symptoms
The immune response rapidly clears the HAV, and patients get a lasting immunity to reinfection
HAV does not cause chronic or persistent infection, and death by HAV is rare
There is a vaccine for HAV, that is safe and very effective
o all children in the US & high risk adults are recommended to be vaccinated against HAV
People exposed to HAV, can be given serum immune globulin (antibody from normal blood
donors)
o Normal serum globulin has lots of anti-HAV antibodies, so it can prevent HAV infection,
or decrease its severity
o Taking a drug like this is called postexposure prophylaxis
Hepatitis B virus (HBV):
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HBV is the only hepatitis virus that has a DNA genome, the rest have an RNA genome
HBV is also unique in that it replicates by reverse transcription
HBV has the smallest genome of any human virus
Infectious HBV virions are surrounded by an envelope with 3 surface antigens (HBsAg-S, HBsAgM, and HBsAg-L)
o The S, M, and L stand for small, middle, and large
o HBsAg-S is the main one of the envelope, and needed to make virions
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HBsAg-L is all of HBsAg-S, plus some more amino acids added
 HBsAg-L is part of receptor binding, and essential for infection
The HBV capsid is made entirely of core proteins called HBcAg, that surround the viral DNA and
the reverse transcriptase
o Reverse transcriptase can copy RNA into DNA
o Reverse transcriptase also has RNase H, which digests the RNA template soon after it’s
copied
o Once the RNA is removed, reverse transcriptase can copy the remaining DNA strand into
double stranded DNA
 In HBV, this step isn’t completed in the infected cell, which is why the DNA in
the virion is only partially double stranded
Blood of people infected with HBV, will have virions, and empty envelopes (aka HBsAg particles,
and they lack the core and genome)
o Most of the empty particles are made of mainly HBsAg-S, and the bigger particles are
called “Dane” particles
o HBsAg is measured to diagnose HBV
Steps of the HBV replication cycle – page 443 pic (after Review with Dr. Meitzner, he said we
wouldn’t be tested on this)
o Once in the blood, HBV travels to the liver and attaches to surface hepatocytes
o After uptake and uncoating, the viral genome is sent to the nucleus, where the partially
double stranded DNA becomes a fully double-stranded, covalently closed, circular
cccDNA
o cccDNA serves as a template for transcription of viral RNA, which is made by host RNA
polymerase 2
o The single viral RNA used for reverse transcription is packaged into an immature viral
capsid, along with viral reverse transcriptase (aka Pol protein)
o Viral RNA is used as the template for reverse transcription, forming viral DNA
o Viral polymerase is the primer for first-strand synthesis, which is why the product DNA is
covalently linked to the enzyme
o DNA filled viral cores then bud through intracellular membranes, to pick up their
envelope of HBsAg, and progeny virions are released from infected cells
Nearly 1/3 of people in the world have been exposed to HBV
In the developed world, HBV is only common in high risk groups, like injection drug users, and
those with multiple sexual partners
In Asia and sub-saharan Africa, 15% of people have chronic HBV infection
HBV is transmitted through exchange of body fluids, like blood, semen, and vaginal secretions
o HBV is also transmitted vertically from mom to baby, due to the baby’s exposure to
mom’s blood during child birth
Primary HBV infection can be asymptomatic, or cause liver injury
o The extent of disease depends on the magnitude of TC cell responses
In 95% of people, the immune response is enough to clear the HBV infection
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In these cases, viral gene products int eh blood decline, and anti-HBs IgG antibodies
appear
 Anti-HBs IgG antibodies provide protective immunity against reinfection for life
The other 5% progress to chronic HBV infection
o They usually have little or no circulating anti-HBs IgG, and viral products like HBsAg and
HBV virons can be found in blood for decades
o The presence of HBsAg in blood for 6 months or more confirms diagnosis of chronic HBV
o Those with weaker immune systems, like newborns, are way more susceptible to
chronic HBV infection
o Some people will suffer episodes of liver injury, called chronic hepatitis
 This is easily seen by elevated serum aminotransferase levels
o After many years of chronic infection, some patients progress to cirrhosis
 Cirrhosis is fibrous scarring of the liver
o Chronic HBV infection also predisposes to the development of hepatocellular carcinoma
(HCC)
In acute HBV, your HBsAg and aminotransferases rise until antibodies are made, and then go
down
In chronic HBV, your HBsAG stay constantly high, and serum aminotransferase levels fluctuate
Page 445 – table 43.4 – how to interpret serologic assays for HBV
There is a vaccine against HBV, that has HBsAg particles made from yeast, and is recommended
for all kids
o The vaccine requires multiple boosters
Also, infants of HbsAg-positive moms, should receive both the HBV vaccine, and anti-HBs IgG
The main drug for years against HBV was interferon-α, a natural antiviral cytokine
o Interferon-α though is expensive, toxic, and has limited effectiveness
o With interferon-α, their circulating viral load decreases, while HBsAg stays positive
o The longer this lasts, the longer the liver still works, even though the infection is still
there
o For most people, the benefits of interferon-α don’t last, and viral levels rebound to high
again once you end therapy
Drugs against reverse transcriptase include adefovir, lamivudine, and tenofovir
o They were originally made against HIV, but work well for HBV
o They also decrease viral load, and more people respond to them than interferon-α
o They’re also easier to take, and cheaper
Hepatitis delta virus (HDV):
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HDV is not a true virus – it’s a subviral agent incapable of infection without help from HBV
HDV’s RNA genome makes only one protein, called hepatitis delta antigen (HDAg)
o HDAg binds to viral RNA and is important in viral replication and assembly
HDV doesn’t code for any envelope proteins, and relies on HBV to provide envelope proteins,
like HBsAg’s S, M, and L, needed for HDV envelope making
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So HDV can only infect people who get HBV at the same time (coinfection) or already had it
(superinfection)
HDV has an increased risk of fulminant hepatitis during the acute phase of hepatitis, and
increases hepatitis severity during the chronic phase
You catch HDV the same way you do HBV, but HDV is less commonly encountered
Once infected, you make antibodies against HDAg, which are used to diagnose it
HBV vaccine also protects against HDV, since HDV need HBV
Hepatitis C virus (HCV):
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HCV is spread by exchange of body fluids
o HCV is often associated and easily spread with injection drug use
o HCV can also be spread by sex, but not as easily
o HCV infected moms can also transmit to their newborns, but this happens less often
than it does for HBV
HCV infection is diagnosed by antibodies against viral proteins, and by finding viral HCV RNA in
blood using PCR
There are many genotypes of HCV, HCV type 1 is the most common in the US
HCV uses a single stranded RNA genome, that is translated into protein after it enters a cell
HCV RNA is not capped, and instead HCV uses an internal ribosome entry site (IRES) at its 5’ end,
as a ribosome binding sequence, that directs initiation of RNA translation
RNA translation makes a big polypeptide that can be cleaved into many functional subunits
Once the HCV polyprotein is processed, viral nonstructural proteins act in genome replication
o One protein called viral RNA-dependent RNA polymerase, copies the positive-sense RNA
into a negative-sense RNA, and then into a positive-sense RNA again
o This process is very error prone, causing a high mutation rate
o So infected people don’t have just one unique virus, but a whole population of related
viruses, called a quasi-species
Liver disease from HCV is milder than that from HBV, especially early
Chronic HCV is just as bad as HBV though
Way more HCV infection progress to chronic (80%) than HBV does (5%)
1/5 of chronic HCV infections lead to cirrhosis, and there is also high risk for hepatocellular
cancer (HCC)
HCV infection can also cause mixed cryoglobulinemia – where antigen-antibody complexes with
virions deposit into kidneys and other tissues, causing inflammation and damage
Treat HCV with interferon-α and ribavirin
o They work, but they’re expensive and hard to tolerate
o 1/5 of patients discontinue due to side affects
o Side affects of interferon-α are fever, joint and muscle aches, low blood cell counts, and
CNS depression
o Side effects of ribavirin are anemia, and it’s a teratogen
Hepatitis E virus (HEV):
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HEV causes food and waterborne hepatitis, especially in the developing world
Like HAV, HEV has no envelope, is single-stranded RNA, and only causes acute disease
HEV is caught the same way as HAV
Symptoms from HEV are usually more severe than HAV, especially in pregnant women