Download Viral hepatitis Epidemiology and Pathology

Pathology
10/7/2008
Viral Hepatitis Epidemiology and Pathology
Transcriber: Don Norris
50:43 (Length of lecture)
Viral hepatitis Epidemiology and Pathology
1:
2: Acute viral hepatitis immunology: 37% of the cases (60,000 cases/year) are caused by Hep A Virus.
44% by HBV. Less numbers by HCV (18%). These viruses only attack humans and lower primates (not
really food borne except HAV if humans touched and infected food)
3: HAV has an incubation period of about 14-45 days (fairly long). 80-90% of children with HAV are
asymptomatic (they will be secreting the virus but you won’t know it-high risk of spreading). In adults,
5-25% are asymptomactic. Most (66%) have jaundice. If you are immunized as an adult you may still
wind up with a disease from Hepatitis A. The usual symptoms are low fevers, malaise, fatigue, anorexia,
nausea (kind of flu-like syndrome), vomiting, pain in upper right quadrant. You can also get
hepatosplenomegaly (enlarged liver and spleen).
Classic symptoms are cholestasis (dark urine from bilirubin). Clay-colored stools from bilirubin in the
stools. 1-5 days later, jaundice develops because of bilirubin in blood. The liver is enlarged and tender.
Liver damage produces increased blood levels of liver enzymes. Often, an immune response is
responsible for the damage caused by the viruses. We detect liver damage by the presence of liver
enzymes in blood.
4: Hepatitis A virus is a circular virus, fairly small.
5: Fecal-oral route of transmission. This broke out in Chinese fast food restaurants not long ago (hot
peppers). They were contaminated at the source by a human. Infected individuals shed virus up to 10
days before symptoms show (people are infecting before they know they are sick). Daycare
transmission of HAV is common. 90% of the kids are asymptomatic (spread without knowing). 25-50%
of adults shed the virus and are asymptomatic. There is no carrier state—once you have acute disease
and get over it you won’t be carrying it and are not infectious.
In most places in the world, it is spread in the water. People all get infected as kids, don’t have much
disease and become immune as adults. Here, we immunize against it to decrease the possibility but we
are not immune because we were not exposed as kids. Eating shellfish is a risk. Oysters concentrate the
particles in the sea water which is where we dump our waste.
6: Hepatitis A virus. In the past we got a vaccine that was licensed in 1995 and since then the cases
have dropped dramatically. We are immunizing at birth for HAV and HBV. This graph shows estimated
and reported cases. Very few of the cases are actually reported (especially the asymptomatic cases).
We have had decrease over last few years due to vaccine.
7: This shows what happens over time when you are infected. You shed the virus in the stool for a few
weeks before becoming symptomatic. Then, you have jaundice and liver enzymes increase (showing
liver damage). Nearly everyone recovers. Antibodies to the virus are formed even before you have
symptoms. If someone has symptoms, you go ahead and look for IgG and IgM antibodies. (IgM are
Pathology: Viral Hepatitis Epidemiology and Pathology
Don Norris
produced somewhat earlier). Once you get to the point that you have symptoms, we can tell you what
you have, but there is not really any treatment for it.
8: Hepatitis E is another fecal oral organism. Not common in US (we don’t even look for it). Older
people in Europe are showing up with it. This is fecal-oral or waterborne. 40% of people in India have
been infected with HEV (most are subclinical). This is a non-enveloped virus with single stranded RNA.
It is a self-limiting disease. No carrier state. Diagnosis is through serology. We can also do PCR on RNA.
9: Hepatitis A mortality is really low for young (less than 5yrs). Even if you are old it is still not very high
(about 1.5% will die of Hep A). Hepatitus E mortality is low unless you get it when you are pregnant
(about 20%). We don’t know why.
10: Hepatitis B is more common in US. It is an enveloped icosahedrons and is very small. It has partially
double stranded DNA w/ very small nucleic acid genome. It has reverse transcriptase, DNA polymerase,
and RNase H (digests the RNA/DNA hybrids and leaves the DNA). This is a major cause of serum
hepatitis in US. Transmission is sexual, parenteral (needle sticks or open cut) and perinatal (mother to
offspring at birth). It is 100 times more infectious than HIV. If someone has both HIV and HBV you are
much more likely to get HBV. This is why we are immunized at birth and take boosters later on. There is
about 100 times more virus per milliliter than HIV. It is also a very tough, infectious virus.
11: Dane particle is the infectious particle and is a very small particle. Surface antigen is what the
vaccine is made out of. Recombinant E. coli makes the surface antigen protein. Hep C antigen is the
core antigen and is inside the cell. E antigen is also related to Hep Core antigen. The DNA is mostly
double stranded, and you can also see the polymerase.
12: The genome is very small (3.22 Kilobases). This is 1/3 the size of HIV. This is one of the few viruses
with more than one protein coded at the same place. If you have a different reading frame in the same
section of the genome, you can get two different proteins. The polymerase takes up a lot of the
genome, but in a different reading frame in the same section it codes for Hep B surface antigen. The
peptase core antigen coding also overlaps with part of the polymerase code. E antigen is over the same
region as the core antigen (C) and actually uses the same reading frame (many of the amino acids are
the same for HBE and HBC).
13: These are the antigens. This is what we make antibodies against. The main HBV antigen is the
Hepatitis B surface antigen (HBsAg) or Australia antigen. It is a glycoprotein. There are three different
sizes (not that important). Three different places that the promoters start and produce different size
proteins. The surface antigen elicits neutralizing antibodies. If you make a good Hep B surface antigen
response, you make good antibodies against Hep B surface antigen and you are immune to the infection
with Hep B.
14: Other antigens: HBcAg: Hepatitis B core antigen is also present and is immunized with the HBsAg
recombinant protein. If you make antibody to the Hep B core antigen, you had been infected by a wild
virus. E antigen is a soluble antigen made from the same transcript as HBcAg but it is released in the
serum. When you are producing a lot of virus, a lot of E antigen is produced. This is a way to measure
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Pathology: Viral Hepatitis Epidemiology and Pathology
Don Norris
how much virus there is in the blood (how infected the person is). If a lot of E antigen, they have a lot of
virus. Recently we have been counting the virus DNA and don’t need to look at the E antigen as a
secondary marker for infection.
15: Incidence in the US: We have a Hep B vaccine licensed in 1980 or so. Since we started vaccine in
infants, the number of incidences has gone down dramatically. Now we are immunizing adolescents as
well and have more decrease. It is decreasing, but there still is a relatively high count at about
2/100,000 people.
16: 73,000 Infections in US/ year. 35,000-70,000 of these infections are symptomatic. Half are
symptomatic (liver enzymes increase). 140-320 deaths (only .2%) per year. 3,000-7,000 have chronic
infections (producing virus for at least 6 months). The surface antigen is circulating in their blood for
more than 6 months. Of the people who are chronically infected, there are 550-2200 deaths per year.
1/3% of US is chronically infected with HBV. Immigrants from Asia have a higher rate of HBV than those
born in the US.
17: The outcome of HepB infections: If baby is infected, 90% end up with chronic infection and will
have it for the rest of its live. One year or so old are much less likely to develop chronic infections.
Immunologically competent adults rarely develop chronic infections, but those that are infected are
more likely to be symptomatic. Immunosuppressed people (HIV etc.) are at risk of chronic infection. If
we could break the link between chronically infected mothers to their infants, we could greatly decrease
the spread of HBV. Many other countries are decreasing the problems by immunizing newborns.
18: Flow diagram. Of those with Acute HepB, 90% will resolve. 1% will have Fulminant hepatitis and
have a good change of dying from liver failure. 9% will become chronically infected (have HBsAg for at
least 6 months). About half of people who chronically infected will resolve and become immune. Some
will become asymptomatic carriers. Chronic persistent hepatitis and chronic active hepatitis are
different levels of inflammation that go along with Hep B. Chronic persistent and especially chronic
active hepatisis can lead to hepatic cellular carcinoma, cirrhosis (continued liver damage) and other
damage caused by virus (polyarteriosis, nodosom, and glomerulonephritis is what you can get from
chronic active hepatitis) .
19: If you are infected with HBV, it takes 4 to 12 weeks before you are symptomatic. The surface
antigen increases and clears when you make anti-core antibody. You are really infected with core
antibody, and later on you make anti-surface antibody. At some point you have antibody to the core,
but not to the surface antigens. When screening blood for transfusions, we would see the blood had no
surface antigen and the surface antibody had not been produced yet (it was in that window). This
blood, however, is still potentially dangerous; but we couldn’t see that it was an issue. Now we check
with anti-hep core antibody to test blood for hepatitis.
20: Chronic carriers are simpler. The surface antigen goes up and stays us. You still make an anti-core
antibody and it stays up. You really don’t make an anti HBsAg. Once they form HBsAg and become
immune, they are no longer a chronic carrier.
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Pathology: Viral Hepatitis Epidemiology and Pathology
Don Norris
21: Here is a panel for acute hepatitis. Anti-HAV is positive if you have had the acute Hep A (IgM is first
and IgG is present). HepB is a little more complex; if you have the surface antigen. From the virus
circulating then it is a very early acute Hep B if you are making antibodies to the core antigen. If you
have a core antibody and no surface antigen, you are in the acute infection and you are clearing it, but
you don’t have surface antibody in evidence yet. You have a convalescent HepB; you have a anti-core
and anti-surface should be positive. Late convalecent can be IgG and you could have actually lost the
anti-HBC surface antigen. Chronic HepB you have IgG to the core and surface antigen. In vaccinated you
only have antibodies to the surface and not the core.
22: HBV viral replication rate. High virion production rate of 1012 to 1013 per day (this is huge). There is
a high mutation rate because there is a lack of proofreading capacity in the hepB reverse transcriptase.
105 substitutions per base cycle. And therefore 1010-11 point mutations in the small virus every day.
Because of the double open reading frames in the virion, there is very few places the mutations will
survive, so there are few mutations actually present. There are still some mutations that exist that
evade the drugs and antibodies that we are using. More common in Asia.
23: Goals of therapy of HBV for someone who is chronically infected: Disease eradication is desired but
not possible (there are extrahepatic reservoirs). Some of the DNA integrates into the host genome. It
doesn’t relapse as long as you have an immune response it doesn’t relapse, but if you don’t have a good
immune response to this surface antigen, you get relapse to HepB. It also has a covalently closed
circular DNA. It is able to reactivate. Once you stop therapy, the virus will come back. It decreases the
disease but does not get rid of the virus. We rely on virosuppressants.
24: HDV is not common in the US. It is in some of our population (IV drug users). It uses the hepB
surface antigen as a coat (this is a defective virus that cannot replicate on its own. It can only multiply in
a person who is infected with HBV. The Delta antigen and RNA are inside the surface antigen of HepB.
25: If you get blood from someone who has both Hep B and D you get a coinfection (acute severe
disease). It is worse acute, but you have lower risk of chronic infection of both Hep B and D.
Superinfection is from being already chronic HBV and then become exposed to someone with hep B and
D you have a high chance of becoming infected with hep D. Without the delta virus, 1-2% of people
become chronically infected with Hep B. If you have blood that has both B and D you have 2.4% chance
of coinfection resulting in chronic disease. If you have chronic Hep B, 91% become infected with Hep D.
26: 20-40 % of HBV carriers in the Middle East and Africa also have HDV. It is low in US (1-10% of
chronic HBV infected are also HDV infected). These are mostly drug addicts, and hemophiliacs. It is also
low in China and Southeast Asia.
27: HCV is a larger virus. It is an RNA virus. There are 9400 base pairs (3x HBV). There are several
serotypes (1-6). The subtypes are not that important. What is important is 80% of US isolates are HCV
type 1. These are more difficult to treat. There is no vaccine for HepC and no obvious immunity from
those who were infected. Most people infected with hepC are chronically infected (85%).
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Pathology: Viral Hepatitis Epidemiology and Pathology
Don Norris
28: 3 million cases of HepC in US. 8,000-10,000 deaths per year are caused by HepC. Transmission now
is occurring mainly in IV drug users. In the past it was more in blood transfusion due to poor tests. Now
it is less common. Cases of hepatocytis carcinoma and liver failure are projected to increase
“dramatically” for 10 - 20 years. The disease takes 10-20 years to develop. We will have disease down
the road from hepC but not new infections. Even now; it is the most common reason for liver transplant
in the US.
29: HCV in the US. The huge amounts in the past (200,000; 250,000; 300,000). Now there are few
accounts of transmission occurring. The acute cases are pretty mild. There are liver enzyme increases,
but really few accounts of jaundice and severe liver disease.
30: In the past, transfusions were up to 20% or so and now it is down to not much at all. Back then we
didn’t know what Hep C was and we called it non-A non-B. Sexually transmission is not common.
Injection drug use is very efficient.
31: Most cases have acute hepatitis. Up to 85% progress to chronic HCV. Less than 2% clear the virus
after they are chronically infected. (in hep B 50% clear after chronic infection). Once you have hep C it is
your friend for life. There is a vigorous humoral and cell-mediated response that causes damage to the
liver instead of clearing the virus. 15% that don’t become chronically infected have a different response.
They are studying it now, hoping it will lead to some sort of immunity. 20% of chronic infections result
in cirrhosis. 25% of the chronic cirrhosis will go on to develop past cellular carcinoma. Alcohol is a
cofactor as is HIV. People who are HIV positive, hepC positive are difficult to care for. These are both
bloodborne pathogens and it is not uncommon for the same people to have both.
32: 15% of those with blood exposure will resolve and 85% will become chronic. 80% of these will be
pretty stable, 20% will develop cirrhosis. 75% of the cirrhosis will be slowly progressive, HIV and Alcohol
increase towards hepatocellular carcinoma (acute cirrhosis). This last category will need to have a
transplant or die.
33: Testing for HCV. There is a very good enzyme linked immune assay (ELIZA). 95% of those with high
reading in the lab will have HCV. A certain percent with low reading will show a false positive. They
should get more testing. The less common the disease, the less common the false positive. Further
testing would be a western blot like test called an Immunoblot assay. It can confirm the less 3.8 low
positives. This is rarely done because 85% of people who infected wind up with chronic infection. So we
would then test the viral load. If they have the virus, you treat them according to the viral load. If they
test negative in the viral load test, you go back and do the immunoblot assay. There are some numbers
on this page that are not important.
34: HCV and Intravenous Drug Users. 15 million illicit drug users. Of these 1-1.5 million are IV Drug
users. 50-80% are infected with HCV within a year of use. They start using drugs and share needles
within a year. Of all IV drug users, 85%-95% are HCV positive. It is recommended that IV drug users not
be treated for HCV because it is difficult treatment and the users might not likely make it.
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Pathology: Viral Hepatitis Epidemiology and Pathology
Don Norris
35: Treatment is interferon and ribavirin for 6 months for non-group 1 (20% of infected), and at least a
year for group 1. Only about 40-50% are cured for HCV. Once you cure someone of HCV they will not
likely relapse. But it is difficult to cure group 1 people. Interfuron causes psychiatric problems and it is
very expensive.
36: Acute viral hepatitis often is asymptomatic. You have elevated serum liver enzymes but you don’t
know it. Symptomactic. Incubation period. Then you have the preicteri stage- has mononuclear type
syndrome and elevated enzymes. By the time you get to the Icteric phase, (have yellow sclera and
jaundice) the other symptoms start to abate. If you have enough liver capacity, you have conjugated
bilirubin - bilirubinemia. Hepatocyte damage results in unconjugated bilirubin which is harder to
excrete. You will wind up with high bilirubin in serum.
37: The liver enzymes. AST is found in liver, cardiac muscle, and skeletal muscle. Any damage to any of
these cells will increase AST. This is not very specific. ALT is more specific for liver damage. You can
look at the ratio between these to see if the damage is in the liver or if it is from something other than
the liver. Gamma glutamyltransferase is high in biliary tree. It also lacks specificity because heart
attacks and kidney failure can lead to high levels.
38: Pathology; this is a diagram of the hepatic globule. There is a central vein where sheets of
hepatocytes are bathed in blood from the branch o f the portal vein and the hepatic artery. The bile
flows the opposite way. You have bile ducts and canalliculi that drains it. This is the arrangement of the
globules.
39: Low power of a normal cell. You can see the triad. The blood flows between the sheets to the
central vein. This is stained so you can see the fibrin around the lobule.
40: A gross picture. Top left is a necrotic area. It is infected with virus and the immune response kills
the cells and you get necrosis. You can see the pale yellow necrosis and collapsed lobules all around
there. Small hemorrhages. This is not a normal looking liver because of the necrosis and damage. The
bottom right is also abnormal due to necrosis and damage
41: If you stain these you can see the amount of inflammation is important. There is a lot of destruction
from the immune response. Infiltrates extend from the portal areas toward the central vein and
obstructs plates. Necrosis destroys a lot of the tissue. If you stain this with antibody to HBsAg and
HBcAg, it is positive for both. You can see that the virus is definitely present. The immune response is
causing the problem. The bottom right shows a sick cell that is undergoing ballooning necrosis. There is
also a dead cell that is shrinking and is picnotic. There is a councilman body (small, dark-staining dead
cell). There are a lot of blood cells around. This is not a healthy looking liver.
42: Fulminant hepatitis leads to massive loss of hepatocytes over 2-3 weeks. There is a lot of
inflammatory cell infiltration. There is exaggerated immune response. Shrunken liver, wrinkled capsule,
collapsed reticulin network of the liver. This is fulminant hepatitis.
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Pathology: Viral Hepatitis Epidemiology and Pathology
Don Norris
43: 80-90% of liver capacity must be lost before severe symptoms of hepatic failure. Drugs and
chemicals that lead to hepatic failure are Tylenol, anesthesias, antibiotics Riphampicin—(isoniazid for
TB), anti-depressants, carbotetrachloride, amanita (mushroom death cap). People who eat certain
mushrooms need liver transplants quickly or they don’t survive.
44: Fulminant hepatitis. You can see the bile staining of the necrotic areas. The consistency is very soft.
45: Fulminant hepatic failure: 50-65% of cases are viral. HBV is most common cause of fulminant
hepatitis followed by HDV-HBV coinfection then HAV then HCV then HEV (pretty rare but more common
in pregnant females. Herpes virus and adenoviruses are non hepatic specific viruses that can cause liver
failure.
46: Chronic hepatitis – portal inflammation is present, plus or minus the interface hepatitis (piecemeal
necrosis) and you get collapsing lobules. They don’t work or drain properly and you get chronic
hepatitis. In portal fibrosis blood doesn’t flow out of the liver. You get linkages (lobules are collapsing
on themselves and lobules that are complete missing). You frequently end up with cirrhosis in chronic
hepatitis.
47: HCV extent of chronic hepatitis can be graded by degree of necrosis and inflammation and fibrosis.
The top left is steatosis, there is a lot of necrosis. You can see the fatty cells. Steatosis is more common
with HCV than any other viruses. Open areas is where fat and liver have been removed.
Bottom right. Is HCV with high stage of infection and extensive fibrosis. There is a lot of collapsed
lobules. A lot of the fibrosis is continuous.
48: Cirrhosis is a diffuse process (all over the liver). Loss of normal architecture is more important than
the damage of the individual cells. Development of fibrous bands, and you have regenerative nodules.
The parenchyma will regenerate, but it cannot regenerate the architecture very well. This causes a lot
of problems.
49: Cirrhosis causes liver failure. There is low synthetic function (you aren’t getting albumin clotting
factors back into circulation so you end up with low protein, low serum albumin and low clotting
factors). Low metabolic function, drug detoxification, estrogen, ammonia. Impaired excretion leading
to jaundice. There is also portal hypertension ascites, shunts, spenomegaly are all things caused by
cirrhosis (non-functioning liver)
50: Macronodular Cirrhosis - nodules are regenerated, but they are not oriented properly, so they can’t
function well. This is recovery after an acute type of disease. Wilson’s disease and alpha-1-antitrypsin
deficiency can also produce macronodular cirrhosis.
51: Low power have a stain that is staining the fibrin. There are very large sections with lobules missing.
52: Post necrotic cirrhosis macrodnodular cirrhosis. Cause of the acute disease is often not determined.
You have regeneration of the nodules and cirrhosis.
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Pathology: Viral Hepatitis Epidemiology and Pathology
Don Norris
53: Hepatitis virus pathology; HCV causes fatty changes. Fatty change is pretty rare with the other hep
viruses. Bile duct epithelium proliferation is common with HCV. HBV has ground-glass hepatocytes.
Under higher power you can see the granular eosinophilic cytoplasm caused by massive quantities of
this surface organism. There is 1012-13 viruses per ml of blood. This is a huge synthetic capacity (lots of
viruses being produced). The nuclei are infected because of the core antigen in the nucleus.
54: Liver tumors: hepatocellular carcimona and cholangiocarcinoma – are both caused by hepatitis
viruses. Cirrhosis winds up with tumors.
55: Here you can see a liver with tumor. Some are hemmorhagic but it is all tumore. cirrhosis and
hepatoma
56: An interesting case here at UAB. There was a kidney transplant that was being investigated because
the donor had transmitted HepC to through many transplants that had come from the same body. 40
year old male alcoholic who died in a cerebrovascular accident (stroke). ALT and AST were normal at
time of investigation. ELIZA was negative for HCV but RNA did show virus after it was tested. 91 organs
and tissues were collected from this guy. 44 of them were put into 40 different recipients. Of the six
organs donated 3 of 3 patients were infected. For the 32 tissue donations, 3 patients had prior HCV
27/5 probable cases - 1/2 saphenous vein, 1/3 tendon, 3/3 bone and tendon, 2 skin and 16 irradiated
bone were all negative. Two corneas – one was prior HCV and the other was negative. You can see how
many people one donor can infect. He probably was in the window period where he had been infected
but was not yet producing antibody. He had a viral load and was infected. Soon we will stream with
PCR to look for viral particle in the tissues.
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