It is not clear to me -- was he UND on maintenance therapy or without any interferon?
For some reason, I can't see that from the article...
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I had the same problem.
When i first read it i thought he was svr.
Second time I thought he was still on maintenance.
In the end decided it didnt matter that much as being UND from Liver Biopsy and Serum but still detectable from kidney was the weird thing for me.
It really is a strange case no matter which way you look at it.
CS
To get the full article you need to subscribe to Liver International. You can get a free 30 day trial.
Whats posted is the full Article minus the Authors and References to shorten it.
I can flick you the complete article if you like.
CS
Yeh I probably should have put more thought into the title. It wasnt that easy to come up with the one I did. Then I only shortened the actual title.
Slowly but surely I am begining to appreciate your views on some of the more obscure aspects of HepC.
CS
I have a hard time following the medical lingo to a 'T' but I'm going to add my input anyway :)
This guy had many problems. He relapsed/non responded a few times.He did monotherapy tx, than peg/Riba tx a few times, then maintenance tx. He had serious illness's, cirrhosis and so on. Did he ever REALLY clear the virus? Could he have been about to relapse? It was coming back, etc? He didn't live long enough to answer that IMO and the entire scenerio is very uncertain from his tx's to his 'clearing the virus'.
Not that I don't consider Occult HCV a very real possiblity (and it scares me so I don't read too much on it!) and I do believe it can be in other organs hiding, etc. but I don't think this guy was a very good subject to base this on. Of course they know more than me, but unless I am missing something , which is likely here, I don't see where it can be sure he ever really cleared the virus as in SVR.
In the studies with cryoglobulin, other issue's I am totally lost. I guess over all it has them paying more attention to and studying Occult HCV more, whatever the situation with the man this all came about from. Even with 12 wk post UND, the thought this virus is living in a kidney, organ makes me shudder!
......Seems an 8 year old post on Breast Implants was more intriguing. Oh Well .....
Hey! I'm still grieving the loss of my tx breast increase here! :)
LL
This thread should probably been titled "HCV reproducing in isolated organs", and it would have stirred up more interest. I think that the subject is very intriguing, and also extremely important. Many of us tend to only think of HCV as a number or value in the blood, by quantity of viral load, and a liver infection measured by stage and grade. When you realize that many other organs are also under assault, and that many deaths from HCV are from causes other than liver failure or HCC, you then realize the importance of better research and gaining a fuller understanding of where HCV resides and what it damages in the body. I wonder how many heart and circulatory failures, or cerebral hemorrhages have been caused by HCV, but never recorded or acknowledged as having done so???
DD
I am not surprised at all by this case, as many of you might suspect. Someone who had previously been HCV positive, over long periods of time, and was treated, finally becoming undetected...would in my estimation be very likely to carry residual HCV infection in other organs or 'reservoirs'. We are not surprised to see evidence of reproducing HCV long after SVR in lymphatic tissue, or sometimes in liver tissues...even though it is usually in very minute, or sub-detectable quantities.
I would similarly not be surprised to see evidence of active, albeit low level, HCV in the brain, spinal fluids, and many other tissues, in those who had longstanding infections and became SVR. I have come to the belief (or conclusion) that SVR and probably spontaneous clearance as well, are both comprised of a bodily system that has ultimately (and possibly permanently) taken 'control' of the virus, either on its own, or with the help of interferon externally introduced, and that has placed the virus into a somewhat 'inactive' or benign state.
I think that the possibility of remote organs, or tissues still carrying a contained, smoldering version of the infection, and never re-infecting the blood or liver, on a full scale, active basis, must be considered. Until extensive research testing on cadavers is done, using extreme amplification techniques, and looking in all of the possible reservoirs where the virus might reside quietly (or not so quietly), we will never know for sure what really happens on a body-wide, system-wide basis after SVR.
By the same token, comments on HCV RNA being in saliva, and other fluids, and not transmitting HCV infection....are very true of course...on the surface. Yes, the virions in these fluids do not seem to trigger active blood/liver infections in those who come in contact with them...but, do they ever cause low-level, isolated CELLULAR infections in these fluids and tissues, that remain reproducing at low levels, in these fluids and tissues, under control of the cellular immune system? This question is being asked by several research studies being planned and conducted by well known Hepatologists. There are ofter apparent 'cellular immune responses' detected in intimate partners of HCV infected persons, in various tissues, fluids, and organs. A few studies have already demonstrated this phenomenon. The follow up studies should go further, to determing is these 'cellular immune responses' to HCV are a result of ongoing localized infection (as in the article above), or due to some other explanation.
I try to keep an open mind, but also suspect that there are other, more benign, and minor modes of infection that may or may not end up being medically significant. I don't think this view is outrageous in any way, since so many questions are already on the radar from the recent research studies on persistence, occult HCV, and other odd viral behaviors. Everything is not always 'cut and dried', and sometimes answers don't turn out to be either black or white. We may have some gray matter ahead. Let's just hope that there is still some left up above!
DoubleDose
Thanks for posting this. I've added it to the 'Occult Hepatitis Health Page':
http://www.medhelp.org/health_pages/Hepatitis/Occult-Hepatitis-C/show/54?cid=64
(though, I was only able to link to the abstract. If anyone has a direct link to the full paper, please let me know).
In the renal paper, they tested via conventional PCR assaying. And as they pointed out, they did not test for negative strand RNA. I don't know for sure, but it's possible that if they had been able to use the mitogen-amplification technique in testing for negative strand that the potential cryo-influence issue may have been moot.
The Parodi paper ("Evidence of occult HCV genotypes in haemophilic individuals with unapparent HCV mixed infections.") seems to raise the possibility that one can be infected with both full-blown Hep C and occult (or multiple genotype occult infections) at the same time.
TnHepGuy
I have an 'uneducated' theory about HCV. I think that it's mode of operation will one day be found to have a lot of similarities to the HIV virus. I mean we're already having meds that are being created that are quite similar to people with HIV and w/triple cocktails, etc. I used to test positive for a very certain and distinctive genotype 1A and 1B. After several treatments, it's testing as 1A. Is 1B really gone? Or is it hiding somewhere? I really, have no way of being 100% sure about it. All I do know is that I've been extremely hard to be rid of this virus and on my current treatment #10, not totally certain that I'll clear it this time either. I want to believe that I'll have a miracle and this will be it. So far, I've had no cryoglobinemia, which I suppose is a good sign. So far, I've had no rheumatoid arthritis, which I suppose is a good sign. I have had a skin disease that came up for which there's no known cure for it and was told that it rarely appears in adults unless they have some type of underlying cancer hemotology. So, dermatologist referred me to a hematologist/oncologist. It was his opinion that I didn't have cancer but that the interferon and/or Ribavirin brought this about. It's called T.M.E.P. for short. The diagnosis was made by a skin biopsy. Recommendations: Avoid sun, hot water, steroidal drugs, insect stings(she gave me an Epi-Pen), exercising in the heat (have to do indoor exercising). Anyway, leave it to me to get 'weird'. Can't help it I guess, I've always 'been a nerd'.
Susan400
It is not clear to me -- was he UND on maintenance therapy or without any interferon?
For some reason, I can't see that from the article...
BTW, based on anecdotal evidence (and somewhat personal), I suspected that polycystic kidney disease may be associated in some cases with hep. C.
Thank you, CS!
While I have nothing to offer that compares with this information when it comes to HCV RNA, it may shed some light as to the role of HVC RNA detected in saliva or other bodily fluids or compartments when comparing the same situation with regards to HIV, in that because it is detected does not make it infectious. I think it entirely possible that the same is true of HCV RNA, which would explain why we don't see more of a co-infection on the part of long-time partners where one has HCV and the other doesn't and they would naturally spend alot of time "swapping spit".
http://www.mcld.co.uk/hiv/?q=HIV%20and%20saliva
Basically, it says the following:
"Occasionally I'm asked about whether HIV is present in an HIV-positive person's saliva, and whether it carries a risk of transmission.
The short answer is that saliva virtually never carries any infectious HIV at all.
It does carry detectable "components" of HIV (such as viral RNA and proviral DNA), but these are not infectious on their own. The environment that saliva provides is far too harsh for infectious particles to remain intact and viable.
There are a number of possible mechanisms that have been suggested, which might explain why saliva seems to be so good at destroying HIV. Specific enzymes present in saliva may be important, or the effect of antibodies in saliva. Additionally, the saliva is "hypotonic" and has a tendency to disrupt any cells which may be floating around in it. It's pretty much certain that it's the combination of these factors that mean HIV is not transmitted in saliva.
It may seem strange that such a dangerous virus can't survive in something as "harmless" as saliva. In fact, saliva is a part of the body's natural defences against infection. Additionally, remember that the HIV virus is actually quite fragile."
Trish
cryoprecipitate - I think it's frozen plasma or blood product.
I just found this:
CRYOPRECIPITATE (CRYO)
When FFP is thawed slowly at 4� C, a white precipitate forms at the bottom of the bag, which can then be separated from the supernatant plasma. This �Cryoprecipitated Anti-Hemophilic Factor� is 15-20 ml in volume and contains: 150-250 ml of fibrinogen, 80-100 units of Factor VIII, von Willebrand�s Factor, Factor XIII, and fibronectin. It is stored frozen and must be transfused within 6 hours of thawing or 4 hours of pooling.
FFP = fresh frozen plasma
If willing sees this he'll explain it to us.
Mike
Yes, that is strange. But, the patient's whole history is strange. This guy certainly had his share of issues. I would like to know if the genotype in his kidney HCV matched his previous liver HCV genotype. I assume that it would but this case is so unusual I don't think it's safe to assume anything.
I couldn't access the article - which hospital did the procedures?
Mike
Good point. Doesnt change that he was UND @50IU for both serum and liver but detectable with presumably the same sensitivity in a kidney biopsy.
And what is cryoprecipitate samples.
CS
My only thought is: Was his liver biopsy PCR sensitive enough to detect the presence of occult HCV? The lower limit of detection was 50 IU/ml and my understanding is that HCV can exist in the liver at a lower VL.
Mike
Definately Mutiple Geno's a higher risk before AIDS campaigns but also up until the early 90s. And yes 60 odd% is high. Surprised me.
Needle and Syringe Programs have definately reduced the risk
Testing of blood products for HCV in the early 90s would have almost eliminated the risk from blood products.
CS
That's very interesting. You would think that there would be a big risk of multiple infection from IVDU prior to AIDS information campaigns. That percentage 62.5% is huge. Could have much broader implications for relapse risk estimation. Do you know why current genotyping techniques aren't suitable for detecting multiple infections?
This is also interesting. Seems HCV is quite good at hidding
Evidence of occult HCV genotypes in haemophilic individuals with unapparent HCV mixed infections.Parodi C, Culasso A, Aloisi N, García G, Bastón M, Corti M, Bianco RP, Campos R, Ares BR, Baré P.
Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
Individuals with haemophilia who received non heat-treated factor concentrates were likely to undergo multiple exposures to the hepatitis C virus (HCV). Therefore, HCV mixed-genotype infections might be more frequent in these patients than in the general population. Their prevalence is extremely variable in similar groups of patients tested by different assays due to the fact that currently available genotyping techniques are not suitable to detect multiple HCV genotypes in a viral population. As an HCV viral reservoir, the peripheral blood mononuclear cell (PBMC) might harbor viral variants distinct from the genotypes detected in plasma.
We investigated the presence of HCV genotypes in a group of chronically infected haemophilic patients in the PBMC compartment using a non-stimulated cell culture system that allows the detection of the HCV genome in culture supernatants.
We compared them to the HCV genotypes found in plasma samples.
Cell culture experiments performed with PBMC demonstrated the presence of additional HCV genotypes that were undetected in the corresponding plasma samples with the same genotyping technique. Although mixed infections at HCV genotype level became evident in 5.6% of the patients (16/288), the culture methodology increased the number of HCV infections with multiple genotypes to 62.5% (10/16) (P < 0.0001).
Once more, the role of mononuclear cells as HCV viral reservoirs is emphasized. Considering minor strains could influence the outcome of treatment, detection of covert HCV mixed-genotype infections might be essential for choosing the adequate therapeutic regimen.
PMID: 18505462 [PubMed - as supplied by publisher]
I thought the article was very interesting but didn't feel qualified to comment. I certainly want as much information as I can get.
What do you think about this part: "important caveat with regard to the diagnosis of occult HCV infection is the potential for cryoglobulin to affect the accuracy of serum RNA detection."
Not that I can suggest anything better, but I have always thought that the testing method - virions in the blood - has an inherent flaw. It is observing a result of the original problem (virions in the blood) rather than the problem itself (HCV infecting cells in various parts of your body).
Very intriguing, such that I'm a bit speechless/wordless on first read of this post. Immediate comment: whoa.
~eureka
I am a little surprised that no one found this article worth commenting on.
I found it intriguing. Seems an 8 year old post on Breast Implants was more intriguing. Oh Well
This article provides a possible explanation of how Occult HCV may occur, and in my view it may also go some way in explaining late relapse.
Ignoring Occult HCV wont make it go away.
CS
Interesting post. Thanks for posting. Mike
Discussion
The presence or absence of HCV RNA in serum is considered a key determinate of chronic HCV infection and successful antiviral therapy. However, there is a growing body of evidence to support the concept of ‘occult’ hepatitis C infection, whereby HCV RNA may be expressed in hepatic and extrahepatic tissues, despite the absence of detectable virus in serum.
Although HCV RNA has been identified in renal biopsy specimens from patients with documented hepatitis C viraemia (1, 2), to our knowledge, this is the first report of HCV RNA detection in renal tissue from a patient who was simultaneously negative for serum and liver HCV RNA. The case highlights a number of important issues regarding the extrahepatic HCV reservoir and its clinical sequelae.
Hepatitis C virus infection is associated with a number of renal pathologies, including cryoglobulinaemic MPGN, non-cryoglobulinaemic MPGN, membranous glomerulonephritis (GN) and MPGN type III (3). A key feature of both the membranous and membranoproliferative subtypes of GN is the renal deposition of immune complexes formed by antibody to HCV and HCV proteins (reviewed in (4)). This cryoglobulin may contain HCV RNA (5) and it is tempting to assume that detection of HCV RNA in the renal tissue of our patient and not in serum was the result of concentration of the viral RNA in accumulating cryoglobulin. However, we were unable to detect HCV RNA in the cryoprecipitate isolated from whole blood, thereby implying that occult HCV RNA was present in renal tissue per se. In support of this theory, renal HCV has been reported in patients without GN (and its associated cryoglobulin), having been detected in renal tissue from viraemic patients with polycystic and hypertensive renal disease (2).
Our patient was receiving maintenance therapy with interferon-α and possibly this led to the preferential clearance of virus from serum vs the kidney, with the re-emergence of replicative virus on occasions when maintenance therapy was withdrawn. An analogous hypothesis might be drawn from the case reported by Coffin et al. (6), where suppression of serum HCV RNA to levels below that detectable by conventional assays was seen in the setting of renal failure and hepatitis B virus superinfection.
What remains unclear is whether a reservoir of HCV might be present in normal kidneys of infected individuals and whether renal HCV is replicative and therefore infectious. We were unable to test for HCV-negative strand RNA (as an indicator of active viral replication), but our observations as they stand should prompt further focused investigation in this important area.
The concept of occult hepatitis C infection is supported by studies reporting evidence of HCV RNA in the liver and peripheral blood mononuclear cells (PBMC) of patients who were thought to have successfully cleared HCV infection either spontaneously or after antiviral treatment (7, 8). Furthermore, Castillo et al. (9) identified hepatocellular HCV RNA in 57 of 100 patients with apparently cryptogenic liver disease, including negative serum HCV RNA. Of these patients, 84% had negative strand RNA, implying active viral replication, and 70% had evidence of viral RNA in their PBMC. Occult HCV also appears to be clinically important. Active viral replication in PBMC from patients with occult HCV has been demonstrated, thereby suggesting potential parenteral infectivity (10), while improvements in liver histology have been observed following treatment of hepatic occult HCV (11). PBMC were not tested in this case, but the lymphatic system might be considered a more common occult site of HCV infection given the evidence from other viral infections such as hepatitis B (12–15).
An important caveat with regard to the diagnosis of occult HCV infection is the potential for cryoglobulin to affect the accuracy of serum RNA detection. According to a recent meta-analysis, 44% of patients positive for hepatitis C demonstrate a cryoprecipitate (16). HCV RNA may be enriched in cryoprecipitate compared with respective serum, with an inverse correlation between the amount of RNA measured in plasma and that in cryoprecipitate (5, 17). Because routinely utilized methods involve the processing of samples at room temperature or lower (18), in patients with cryoglobulinaemia, a greater amount of viral RNA may separate with the pellet during serum preparation for PCR-based HCV detection.
Clearly, this has implications for quantitative assessment of HCV RNA, but it has even been proposed that the presence of cryoglobulinaemia might result in a false-negative assay for serum HCV RNA. Van Thiel et al. (19) showed that samples from HCV patients with either ‘low’ (<106 genomes/ml) levels of serum HCV RNA or large amounts of cryoglobulins could be rendered negative for HCV RNA by precipitation and removal of the cryoglobulin. It is unclear as to how applicable these findings are to patients tested with the much more sensitive assays currently employed, but the absence of HCV RNA in the cryoprecipitate of our patient strongly supports the presence of true occult HCV.
We have reported an apparently unique case of HCV RNA identified in the kidney, despite the absence of detectable serum or hepatic virus. Given the widespread reliance on serum HCV RNA as an indicator of chronic hepatitis C infection and the success of antiviral therapy, this finding may have significant implications for the clinical management of such patients, especially those with concurrent renal disease.
CS