Hepatitis B and carcinogenesis

[bomgd3]

---

Members do not see this ad.

Hey everyone,
I'm taking my boards next Friday and I am still having some trouble with how HBV causes cancer. I've read that it is due to repeated cell death/regeneration cycles, due to DNA integration, or due to the HBx protein. It's a very confusing topic, and all of my review sources just go through the serology of HBV but not the pathophysiology. Robbins is unclear, too. I've gotten multiple UWorld and other questions on this topic so it seems like fair game.

Thanks in advance!!

 

[AngryBird69]

Hey everyone,
I'm taking my boards next Friday and I am still having some trouble with how HBV causes cancer. I've read that it is due to repeated cell death/regeneration cycles, due to DNA integration, or due to the HBx protein. It's a very confusing topic, and all of my review sources just go through the serology of HBV but not the pathophysiology. Robbins is unclear, too. I've gotten multiple UWorld and other questions on this topic so it seems like fair game.

Thanks in advance!!

Bom my understanding is that it causes DNA instability by repeated DNA integration.

 

[Chaoticsheath]

Uworld says HBx(some interaction w/ p53???) and DNA integration into the genome, which i guess generally F's shyt up.

sorry don't know what to tell you. just look for those ground glass cells and click the circle that says hbv next to it.

 

[Phloston]

My understanding is that the diffuse apoptoses induced by CD8+ T-cells, based on the elimination of viral infected cells, induces regenerative hepatocellular hyperplasia, leading to increased mitoses (as you've said) and an increased probability of error.

Hepatocytes are stable cells, so increased time spent G0 --> G1 is causative.

Aflaxotin from Aspergillus (in peanuts) is a synergistic risk factor.

Unlike with HepC, HepB usually does not demonstrate cirrhosis prior to cancer development. If the pt has cirrhosis and cancer and the vignette is otherwise non-specific as to whether it could be HepB or C, it's C, not B.

 

[HelpPleaseMD]

I have a follow up question. If a vignette describes a person who has been infected with a strain of Hepatitis that can cause cirrhosis how can you tell if its hep B or hep C when the infection is acute? (there was a UWORLD question on this... I just forgot the answer). One of the two infections has a more severe presentation.

 

[Phloston]

I have a follow up question. If a vignette describes a person who has been infected with a strain of Hepatitis that can cause cirrhosis how can you tell if its hep B or hep C when the infection is acute? (there was a UWORLD question on this... I just forgot the answer). One of the two infections has a more severe presentation.

Hm interesting. Without looking this up, I don't know. I didn't know one has a more severe acute presentation. The only thing I could think of to differentiate them is that the HepB incubation is 4-26 wks whereas HepC is 2-26 wks, so HepC would should up first. If it shows up first, I would reckon it comes on more strongly, so I would go with that one as more severe initially.

Once again though, I have no idea.

 

[ijn]

I have a follow up question. If a vignette describes a person who has been infected with a strain of Hepatitis that can cause cirrhosis how can you tell if its hep B or hep C when the infection is acute? (there was a UWORLD question on this... I just forgot the answer). One of the two infections has a more severe presentation.

If the acute presentation seems at all severe, then it's most certainly Hepatitis B. Hepatitis C has a fairly mild acute presentation with nonspecific symptoms - fatigue, arthralgia, and no jaundice.

 

[Phloston]

If the acute presentation seems at all severe, then it's most certainly Hepatitis B. Hepatitis C has a fairly mild acute presentation with nonspecific symptoms - fatigue, arthralgia, and no jaundice.

Could you be more specific? What's the mechanism / presentation, and how does it differ from HepC's?

 

[HelpPleaseMD]

Thanks ijn. that is what I vaguely recalled

 

[iCY]

I have a follow up question. If a vignette describes a person who has been infected with a strain of Hepatitis that can cause cirrhosis how can you tell if its hep B or hep C when the infection is acute? (there was a UWORLD question on this... I just forgot the answer). One of the two infections has a more severe presentation.

???? look @ serology? HBsAg indicates hepatitis B infxn lol Also look @ the source of transmission & the risk factors. Hep C = needles/junkies, blood transfusions. Hep B = sexual & maternal-fetal

 

[HelpPleaseMD]

lol ICY. what you say is true but the question didn't provide that information

 

[Phloston]

???? look @ serology? HBsAg indicates hepatitis B infxn lol Also look @ the source of transmission & the risk factors. Hep C = needles/junkies, blood transfusions. Hep B = sexual & maternal-fetal

iCY, I haven't seen you on here in a while. I've been missing the love and motivation you've offered up through previous posts.

 

[ijn]

Could you be more specific? What's the mechanism / presentation, and how does it differ from HepC's?

I mean, at the very basic level you're not going to have a guy come to your clinic with an acute Hepatitis C infection. He's probably going to present once his cirrhosis becomes symptomatic (or maybe he is told he's Hep C positive after donating blood to pay for more heroin or something...). It's a slow and insidious virus.

Hepatitis B is associated with severe acute infection (jaundice, myalgia, arthralgia, fever, pruritus, fever, etc.) that spontaneously resolves in most cases. Hepatitis C is associated with a mild, nonspecific acute stage that goes chronic in the vast majority of patients. I don't think the exact mechanism matters. I think it's more important to know the natural history of the disease.

 

[Phloston]

I mean, at the very basic level you're not going to have a guy come to your clinic with an acute Hepatitis C infection. He's probably going to present once his cirrhosis becomes symptomatic (or maybe he is told he's Hep C positive after donating blood to pay for more heroin or something...). It's a slow and insidious virus.

Hepatitis B is associated with severe acute infection (jaundice, myalgia, arthralgia, fever, pruritus, fever, etc.) that spontaneously resolves in most cases. Hepatitis C is associated with a mild, nonspecific acute stage that goes chronic in the vast majority of patients. I don't think the exact mechanism matters. I think it's more important to know the natural history of the disease rather than the why.

Ijn, I'm a little surprised by this statement here. We all know the USMLE is about knowing the "whys."

HepC, although known to have one of the longest Hep incubations by hitting 26 wks in some cases, can also present at 2 wks, which is prior to the earliest of 4, which can be seen with HepB.

***My guess would have to be that if HepC leads to chronic infection in 80+% of cases, then it means the CD8+ T-cell response is generally not as effective to begin with at controlling the virus. Since most HepB cases resolve, the CD8+ response must be more salient with B vs C, which would explain HepB's potential stronger initial symptoms relative to those of C.

 

[iCY]

iCY, I haven't seen you on here in a while. I've been missing the love and motivation you've offered up through previous posts.

👍 been studyin. test in 2 days, ready to get on with my life & move past these boards

 

[ijn]

I think you're losing site of the forest for the trees. Like you've memorized the weeks of presentation of Hep B vs C, but you didn't learn about the actual natural history of the two diseases - one is chronic and the other is acute and self-limited. For the STEP 1 knowing the latter fact is about a million times higher yield.

We know Hepatitis C undergoes significant antigenic variation so you never develop protective antibodies to help in viral clearance, whereas Anti-HBs antibodies are protective. I guess I could see them writing a question on that. I have never read anything about relative the CD8 responses between the two viruses.

 

[Phloston]

I think you're losing site of the forest for the trees. Like you've memorized the weeks of presentation of Hep B vs C, but you didn't learn about the actual natural history of the two diseases - one is chronic and the other is acute and self-limited. For the STEP 1 knowing the latter fact is about a million times higher yield.

We know Hepatitis C undergoes significant antigenic variation so you never develop protective antibodies to help in viral clearance, whereas Anti-HBs antibodies are protective. I guess I could see them writing a question on that. I have never read anything about relative the CD8 responses between the two viruses.

It makes sense that the CD8+ response would have to be stronger with HepB vs C. This is not only with respect to the initial more salient presentation, as we've touched upon, but also based on the fact that HCC occurs in B without cirrhosis whereas it follows cirrhosis in HepC. This means the rate of regenerative hyperplasia secondary to CD8+-mediated diffuse apoptosis must be greater with B.

The antigenic variation component of HepC, however, is a good point as far as carrying this a step further to explain why the CD8+-response would be lesser relative to HepB.

And I also enjoy your forest/trees comment. I appreciate the entertainment.

Btw, the incubation times are easy to remember for the Heps because they alternate 2 4 2 4 2 for the first numbers, then 6 7 8 for A D E, but 24 and 26 for B and C for the second numbers.

 

[teenmachinery1]

It makes sense that the CD8+ response would have to be stronger with HepB vs C. This is not only with respect to the initial more salient presentation, as we've touched upon, but also based on the fact that HCC occurs in B without cirrhosis whereas it follows cirrhosis in HepC. This means the rate of regenerative hyperplasia secondary to CD8+-mediated diffuse apoptosis must be greater with B.

The antigenic variation component of HepC, however, is a good point as far as carrying this a step further to explain why the CD8+-response would be lesser relative to HepB.

And I also enjoy your forest/trees comment. I appreciate the entertainment.

Btw, the incubation times are easy to remember for the Heps because they alternate 2 4 2 4 2 for the first numbers, then 6 7 8 for A D E, but 24 and 26 for B and C for the second numbers.

Hey Phloston- I know that HCC _can_ occur via Hep B without developing cirrhosis but I thought usually, even with HBV, you develop cirrhosis before HCC. What am I missing here?

 

[teenmachinery1]

Uworld says HBx(some interaction w/ p53???) and DNA integration into the genome, which i guess generally F's shyt up.

sorry don't know what to tell you. just look for those ground glass cells and click the circle that says hbv next to it.

Yeah, UW says:

1) there is increased inflammation and regeneration thus an increased rate of mutations
2) HBx protein or whatever activates "growth factors," essentially mucking up repication regulation
3) HBx protein owns p53 in the face, further mucking stuff up.

 

[ijn]

I guess you can use that as a rough rule - if you see HCC in the absence of cirrhosis then it's probably caused by Hep B. However HCC induced by Hep B can come from both cirrhosis and non-cirrhosis pathways. 5-10% of chronic infections progress straight to HCC while 2-6% of chronic infections progress undergo cirrhosis with subsequent development of HCC.

 

[Phloston]

Hey Phloston- I know that HCC _can_ occur via Hep B without developing cirrhosis but I thought usually, even with HBV, you develop cirrhosis before HCC. What am I missing here?

I had come across this in a practice question somewhere (I think USMLE Rx), and the distinction was made between B and C based on C almost always demonstrating HCC after cirrhosis sets in, whereas that's not the case for B.

 

[Phloston]

Yeah, UW says:

1) there is increased inflammation and regeneration thus an increased rate of mutations
2) HBx protein or whatever activates "growth factors," essentially mucking up repication regulation
3) HBx protein owns p53 in the face, further mucking stuff up.

I hadn't heard of HBx before, so thanks for posting that. Maybe I'll encounter it when I eventually get to Kaplan/UWorld.

 

[MrBeauregard]

As other have stated, both Kaplan and UWorld stressed the fact that the HBx protein from Hep B is important in the pathogenesis of HCC due to its inactivation of p53. The increase in cell cycle progression leads to the increased likelihood of mistakes.

With HCV, UWorld stressed that the RNA-dependent RNA polymerase lacks 3'-->5' exonuclease activity, thus making it unable to repair mistakes. This increased rate of mutations means that the immune system is never seeing the same virus and the protective antibodies made previously are no longer protective. This leads to chronic infection in the majority of cases and thus predisposes to HCC.

Neither Kaplan or UWorld mentioned anything about the CD8+ T-cell response to either virus or its role in the pathogenesis of HCC.

 

[Phloston]

As other have stated, both Kaplan and UWorld stressed the fact that the HBx protein from Hep B is important in the pathogenesis of HCC due to its inactivation of p53. The increase in cell cycle progression leads to the increased likelihood of mistakes.

With HCV, UWorld stressed that the RNA-dependent RNA polymerase lacks 3'-->5' exonuclease activity, thus making it unable to repair mistakes. This increased rate of mutations means that the immune system is never seeing the same virus and the protective antibodies made previously are no longer protective. This leads to chronic infection in the majority of cases and thus predisposes to HCC.

Neither Kaplan or UWorld mentioned anything about the CD8+ T-cell response to either virus or its role in the pathogenesis of HCC.

The CD8+ component is just intuitive, since that would be a part of the immunological response to both. I've given my reasoning above.

Good points about HepB and C from Kaplan/UW. Thanks for posting those.

 

[futuredoctor10]

As other have stated, both Kaplan and UWorld stressed the fact that the HBx protein from Hep B is important in the pathogenesis of HCC due to its inactivation of p53. The increase in cell cycle progression leads to the increased likelihood of mistakes.

With HCV, UWorld stressed that the RNA-dependent RNA polymerase lacks 3'-->5' exonuclease activity, thus making it unable to repair mistakes. This increased rate of mutations means that the immune system is never seeing the same virus and the protective antibodies made previously are no longer protective. This leads to chronic infection in the majority of cases and thus predisposes to HCC.

Neither Kaplan or UWorld mentioned anything about the CD8+ T-cell response to either virus or its role in the pathogenesis of HCC.

Good post! It makes sense that due to the increased mutation rate with HCV, lack of protective antibodies leads to chronic infection in the majority of cases. There are two World questions on the most likely outcome following HBV or HCV infection:

Hep B infection: likely an acute hepatitis that resolves (if contracted by an adult*)
Hep C infection: stable chronic hepatitis

*I say if contracted by an adult, since infants who acquire infection in utero are responsible for most of the chronic carrier states of Hep B