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Occult HCV infection: an unexpected finding in a population unselected for hepatic disease.
De Marco L, Gillio-Tos A, Fiano V, Ronco G, Krogh V, Palli D, Panico S, Tumino R, Vineis P, Merletti F, Richiardi L, Sacerdote C.

Unit of Cancer Epidemiology, C.E.R.M.S., University of Turin, Turin, Italy. gilliotos_demarco***@****

BACKGROUND: Occult Hepatitis C virus (HCV) infection is a new pathological entity characterized by presence of liver disease and absence or very low levels of detectable HCV-RNA in serum. Abnormal values of liver enzymes and presence of replicative HCV-RNA in peripheral blood mononuclear cells are also observed. Aim of the study was to evaluate occult HCV occurrence in a population unselected for hepatic disease. METHODOLOGY/PRINCIPAL FINDINGS: We chose from previous epidemiological studies three series of subjects (n = 276, age range 40-65 years) unselected for hepatic disease. These subjects were tested for the presence of HCV antibodies and HCV-RNA in plasma and in the peripheral blood mononuclear cells (PBMCs) by using commercial systems. All subjects tested negative for HCV antibodies and plasma HCV-RNA and showed normal levels of liver enzymes; 9/276 patients (3.3%) were positive for HCV-RNA in PBMCs, identifying a subset of subjects with potential occult HCV infection. We could determine the HCV type for 8 of the 9 patients finding type 1a (3 patients), type 1b (2 patients), and type 2a (3 patients). CONCLUSIONS: The results of this study show evidence that occult HCV infection may occur in a population unselected for hepatic disease. A potential risk of HCV infection spread by subjects harbouring occult HCV infection should be considered. Design of prospective studies focusing on the frequency of infection in the general population and on the clinical evolution of occult HCV infection will be needed to verify this unexpected finding.
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Avatar_m_tn
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Avatar_f_tn
Thanks, that's where I got it. Any thoughts on it?
Ever since I read that first article on occult Hep C for SVRs and people with high LFTs of unknown origin and no antibodies or HCV RNA detectable in blood, I immediately thought: what about no antibodies, no HCV RNA and NORMAL LFTs? If the virus level is that low that it doesn't trigger a detectable antibody response and there's no blood viremia... isn't it also possible that it does not cause enough damage in the liver to cause abnormal LFTs?? That seemed like a logical possibility to me and here's the first study documenting it...

In my personal case I have been suspecting HCV based on some hepatic and many extra-hepatic symptoms I have been having for 4 years now. Yet I never got a clear diagnostic and I've been told by many doctors to treat my anxiety as my hepatitis symptoms and fears are imagined. In a way after all these recent studies have been published I'm starting to feel relieved that I'm not a nutcase. I would still very much like to get a diagnosis. Does anyone know a commercial lab in Europe where I can pay to get the PMBC HCV RNA test?

Thanks in advance.
EE
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Avatar_m_tn
I have no idea where you could get tested for 'Occult HCV" here in the US or abroad. I am not even sure about what they would test - blood, PMBCs or liver tissue and whether and, if so, with what agent, the cells would need to be stimulated. This is way over my head. I just read the articles and make what I can out of them. I would think that the majority of HCV patients who have achieved SVR status have read about the durability of SVR and find some degree of comfort in that. Occult HCV for me is an academic issue and I know nothing about who, how and where testing is done.
Mike
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Avatar_f_tn
Oh, and one more thing. I've read a discussion thread where DD and TnHepGuy were wondering if there's a difference between primary occult infection and persistent infection after svr.
Personally I don't think there is. I'm basing my statement on personal observations of what's been happening in my body for the past 4 years. The primary occult is just the immune system keeping the infection in check on its own, without the help of treatment. It could either be due to a very reactive immune system or to the infection route (not blood-to-blood). Post SVR occult infection is getting there with extra help - keeping it in check and not allowing it to produce serious liver damage.
I do believe there are different degrees of damage by occult infections - very little (in my case I've never had abnormal LFTs although they varied quite a bit for a while), moderately high LFTs etc. It's just different shades of gray...
But the bottom line is the virus is never completely erradicated from the system and its presence can be seen in different types of discomforts and manifestations. I have seen improvement over the course of years - the RUQ discomfort is much easier to bear than it used to be in the first couple of years, my skin manifestations are more rare, however they always return. For a while I was hoping they will disappear for good but it hasn't happened. I now think I'm stuck with them for life. My only concern now is how contagious it actually is...
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Avatar_m_tn
I'm not sure that I agree with that but it's not important that I do.
Your situation is different than most I have read about. The majority of case I have read about involve a documented case of HCV which resolves either spontaneously or as a result of antiviral treatment. If I understand you correctly you have never shown antibodies or viral load.
I hope DD sees this because I am sure he'll be interested and have an opinion.
As I said, it is purely an academic issue for me and I have no opinion about your case.
Mike
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It's interesting that the study refenced in this thread is from the University of Turin and on a subject that is shrouded in mystery, controversy and the stated need to investigate further, as many of the studies mention.

But, I think that I read quite a leap from expereincing different types of discomforts and manifestations to how contagious it might be when there is no evidence of an infection or even antibodies.
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Avatar_f_tn
No, I've never had a detectable level of antibodies (I've had some, but not enough to qualify as "reactive"), no detectable viremia on 2 HCV RNA tests and no abnormal LFTs (the levels were rising for a while until double then went down but never to the same level as on first test).
However, all the clinical symptoms were hepatitis symptoms - rash, nausea, diarrhea, light stool colour, darker urine, malaise, loss of appetite, RUQ discomfort (interestingly the discomfort started later than the rest of the symptoms and worsened while the LFTs were rising). But the most persistent of all is vasculitis - all sorts of blood vessel abnormalities that appear mostly on legs and sometimes on arms: red dots of different sizes and bruises.

I just wish I could get a definite diagnosis as it does not seem to go away for good as I was hoping for.

EE.

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Avatar_f_tn
If the latest research is valid, which I believe it is, we will have to reconsider what qualifies as "evidence of an infection" in the case of this weird virus. I'm not trying to make any definite statements here. I'm just saying there's a lot of unexplained things going on which I have been experienced first had for the past 4 years and which may require a different approach to understanding the way this infection works.
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Avatar_f_tn
Why would you convince yourself that it has to be associated with occult hepatitis C?  All your PCR"s were negative.  Perhaps your doctors are correct and it may be a very wise and economical to treat the anxiety.  Why not autoimmune hepatitis or occult hepatitis B?  Vasculitis is associated with many other disorders and there are many types of vasculitis.  It's like looking for a needle in a haystack.

Diamond_Lil
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Turin, shroud.  Very very funny!!
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Avatar_n_tn
the DeMarco paper out of Turin and the Nicot paper from Toulouse that Mike posted previously are the last two salvos in this argument with the French arguing "mais non!" and the Italians "ma si!" (but Toulouse isn't all that far from Fatima so maybe FlGuys's on to something here).  

Re PBMC testing in Europe, one of your best bets may be contacting one of the authors of the Spanish papers (Castillo, Carreno, etc.) who fervently believe in lymphotropic HCV For example see:
http://www.ncbi.nlm.nih.gov/pubmed/19475603

In the US, it might be worth contacting  Balan at the  Mayo Clinic :
http://www.ncbi.nlm.nih.gov/pubmed/18594984

The larger question however, is that even if this real and correlates with observed symptoms, there's not much to be done about it. I'm not aware of any options for eliminating sub-clinical HCV - though this may prove to be amenable to the new drugs coming to market.

BTW the latest review on the ongoing controversy is
http://www.ncbi.nlm.nih.gov/pubmed/20070513

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Thanks for your comments, Everyone!

Willing, yes, that's how I've looked at it for the past 4 years too: even if it's caused by HCV there is not much to be done about it. My immune system is doing a pretty good job on its own so probably 99% of hepatologists would be against any treatment in my case. Plus since I was seeing some very slow improvement over the years I was hoping that eventually it'll go away. Well, I'm not so convinced any more. My vasculitis is not going anywhere, on the contrary, it seems to be getting worse. And I'm still noticing people getting sick with digestive symptoms after being around me for a while. So whatever I have is still in my system and still infectious. I need to find out what's causing all this.

Another interesting article is this one: "Hepatitis C virus lymphotropism and peculiar immunological phenotype: effects on natural history and antiviral therapy".
"The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, easily detectable by searching simple laboratory and clinical parameters, mainly represented by vasculitis-like skin features and hypocomplementemia."
It seems to describe my situation - vasculitis and lower C3 complement levels. I also have positive autoimmune and anti-smooth muscle antibodies.

I am aware this is cutting edge research and there's a lot to be uncovered. All I'm saying is let's keep an open mind and keep searching for answers.
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Avatar_n_tn
before spending money and time on HCV PBMC testing you might want to take a look at the Marukian'08  paper from
the Rockefeller institute
http://www.ncbi.nlm.nih.gov/pubmed/19003912
mentioned at the bottom of that old thread (it's free access)

This was the paper that convinced me that a lot of HCV detection in PBMCs is likely to be a bystander effect rather than evidence of active replication. Figure 2 makes a pretty strong point. They infected liver cells and a variety of PBMCs with a fixed dose of virus at day 0 (amount of virus flagged as black triangle ) then cultured them side by side for 4 days each day extracting and measuring HCV RNA  from both cells and supernatant.  Two cell conditions were examined and in one they added an anti-HCV agent (2'CMA) that blocks the same viral protein as R7128.
In *every single instance* the plots show the same trend : HCV RNA increases only in the liver cells in the absence of the drug. In all other cell cultures the amount of RNA, though readily detectable,  stays flat or decreases. RNA level in PBMCs closely matches that of liver cells in which HCV can't replicate because of the drug.  (and they report the pattern shown matches that from 3*10 replications of the experiment)

If you were trying to convince a jury, this looks close to  beyond a reasonable doubt to me. The PBMC-detected RNA is likely bound to the cell receptors rather than actively replicating. Of course there's always some room for doubt, maybe replication occurs at a very low-level or additional factors, not available in cell culture, are required for replication in PBMCs.

However, if you're determined to go through with this, it might make more sense to have them check for RNA in cells from a bx.
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Avatar_f_tn
Thanks for the article suggestion. I could only get the abstract, though.
I do see your point. However, my idea was to test for the presence of HCV RNA in PBMCs (instead of liver) and not necessarily to test if the virus is also replicating in PBMCs. Please correct me if I'm wrong, but my understanding was that they can now test for the presence of the viral genetic material in PBMCs which is equal to a diagnosis, isn't it?
EE
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Avatar_f_tn
I am not sure why you are so convinced that all your symptoms are HCV related. Have they tested you for all possible autoimmune disorders that can cause vasculitis? gallbladder disorders? C-difficile infection, etc.
It is stretching it to  have focused on one particular disease with no positive proof from antibody tests, (antibodies are either there or not, the range is positive or negative, not maybe). If one assay is not definitive ask for another, and if no antibodies, or VL is detected, search for other causes, don't get stuck on one disease. You might miss getting treated early for something serious. It seems that the occult HCV is tied to individuals that tested pos for the disease at some point. If you have good insurance, ask for tests for other illnesses, like vasculitis of the gallbladder (which is an organ in the area of the liver), AIH, or any other disease that can cause vasculitis.  I hope you have good insurance, though.
GL
hello willing! so DD is still around with the theory? I am glad for the study that found nothing in the renal patients post tx. I guess the controversy will go on no matter what. good to see you!
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Avatar_f_tn
Thanks for the comment. I have been testing for a lot of things... all sorts of bacteria and a few viruses, WBC, gallbladder ultrasounds, etc. They've never been able to make a definite diagnosis. Judging by clinical observation and present autoantibodies, doctors could only tell me that there are only two certain things about my condition:
1. an autoimmune component; 2. a liver component. Something is affecting my immune system and my liver. So I started reading and it seems that generally hep C and B can cause hepatitis and immune system disorders. Since I don't have the regular blood markers I started looking into the occult discussions. It seems that occult hep B means HBV DNA detectable in blood (I took the test, don't have it). While hep C seems to be the hardest to diagnose in certain cases. I would only like to take a test to rule it out if possible.
I would be the first to live it alone but the infection is ongoing after 4 years and it seems to be contagious under certain conditions.

If you have any other idea of what I could test for that causes liver inflammation and autoimmunity I would very much appreciate it. Or any suggestion of a specialist that I can talk to over the internet or in person (I live in Europe).

Thanks again for any input on this.
EE
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Avatar_n_tn
LL201: you should be able to get the full Marukian study by clicking on the "Free - Author Manuscript" icon on the right-hand border. I understood you were interested in PBMC testing as a possible reservoir of low-level HCV replication. However if you're just checking for presence of virus, sensitive testing in serum should be sufficient. Once again, one of the authors of the the Spanish occult-hcv papers might be the best contact in Europe eg
http://www.ncbi.nlm.nih.gov/pubmed/19523175

I agree with others that this seems a bit of a stretch, but can understand wanting to rule it out. DD did post an interesting article a while back,  based on a study  done in Egypt, that found different HCV-related cytokine profiles among family members exposed to HCV. However that seemed to indicate a sort of immune  system "bristling" at the nearby virus more than actual infection.

Cuteus: nah, haven't seen any posts by DD in a long while - perhaps he's lost interest. It's good to hear from you; I hope you are keeping well!
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