New Occult Hep C paper from Pham et al

[TnHepGuy_]

Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles.

"Hepatitis C virus (HCV) replicates in immune cells in both chronic hepatitis C (CHC) and occult HCV infection, but the extent of virus replication in this compartment in these opposing infection forms varies greatly. It was unknown whether this could be linked to HCV genotype or to differences in host gene expression shaping the immune response, and whether HCV replication in immune cells is sensitive to endogenous antiviral cytokines. In this study, we uncovered that significantly greater HCV load in peripheral blood mononuclear cells (PBMC), but not in plasma, coincided with HCV genotypes 2 and 3 in CHC, but with genotype 1 in residual occult infection after clinical resolution of hepatitis C. Moreover, PBMC from individuals with occult infection transcribed significantly greater levels of IFN-alpha, IFN-gamma and TNF-alpha, but less interleukin (IL)-10 than those from CHC. In CHC, PBMC with low HCV load expressed significantly more IFN-gamma but less IL-12 than did cells with high virus content. In occult infection, HCV RNA detection in PBMC was associated with much lower IFN-alpha and IL-12 expression. Further, HCV replication in T lymphocytes could be completely eliminated by activation of endogenous IFN-gamma in CHC, but of IFN-alpha in occult infection. In conclusion, CHC and persistent occult HCV infection are characterized by clearly different profiles of antiviral cytokine response in circulating immune cells which are also different from those of healthy individuals. Higher expression of IL-10, combined with lower transcription of IFN-alpha, IFN-gamma and TNF-alpha, is associated with a more robust HCV replication in immune cells."

http://www.ncbi.nlm.nih.gov/pubmed/19215578?ordinalpos=1&itool=Email.EmailReport.Pubmed_ReportSelector.Pubmed_RVDocSum


TnHepGuy

[DoubleDose]

Thank you so much for your informative reply.  You have provided more specifics and insights on how PD works than the specialists that I have seen.  I may conduct my own trial with the Curcumin over a long period.  I have already added daily Vitamin E, Acetyl-L-Carnitine, Primrose Oil, L-Arginine, L-Citrulline, and assorted other supplements, for the last nine months....and am seeing some slight improvement which may or may not be a result of the supplements.  Thanks again for your interest.

DoubleDose

[geterdone]

Laymen here,

So what you are saying is that while treating the virus with high doses of interferon these strands of RNA are cleaved up, but all are not totally destroyed by the t cells and are floating around in the peripheral blood and organs and are still giving off a signal in a mutated state by which the now altered natural interferon is still attacking anything with its signature in an undetected state?

Could it be that during the duration of treatment with the synthetic interferon and its “additives” that it by some chance altered the natural gamma interferon from its natural state in which it has left it in an overstimulation state there by causing just as much long term damage as the virus itself but on a lower chronic level?  

jasper

[Hepatitis Researcher]

While TNF alpha might have a role in the progression/promotion  of Peyronie's disease it does not seem to be the primary player. This fairly frequent syndrome (5%) might be caused by a genetically predetermined propensity of excessive TGF beta expression under conditions where the body tries to heal by scarring even minor traumatic injuries. Thus minor traumatic injuries to the tunica albuginea are responded to with excessive progressive scar tissue formation. TGF beta is a critical 'cytokine' or tissue hormone that acts to "heal" injuries by promoting scar formation

Certain cytokines levels will have a promoting role in that setting, however the effect of inhibiting specific ones like TNF alpha is hard to predict and you will have a difficult time finding a doctor prescribing one of the TNF alpha inhibitors for this purpose, since regression is - even if there is a positive effect- going to take substantial time. There will also be the argument that TNF alpha inhibitors shall not be used in patients with hepatitis, even if SVR, I presume.  There is literature describing an inhibitory effect of trans Resveratrol on TGF beta expression and Curcumin might be useful in reducing the intensity of the profibrotic pathway signaling that results from increased TNF alpha levels, but of course there are no trials to prove any effectiveness of these in this particular disorder.

[Rockerforlife]

Dont know if this is any help,but there is a natural product out there that modulates and balances the immune system....its called 'moducare"

[DoubleDose]

You just commented on something which connects with another problem which I have developed in the past year, now that I am 5 years post-tx, and SVR.  I have developed Peyronies Disease, which is in effect, a fibrotic, or scar tissue affliction in the penis, causing a curving.  In recent research studies published by the Urologists Association, it seems that increased levels of circulating cytokines, and specifically TNF-Alpha, have recently been correlated to a very high degree with those who have Peyronies.  This is a disease with no currently understood cause, and only lately is getting lots of research attention.  Of course, I have to consider my post-tx auto-immune reactions, and plethora of symptoms after SVR, in thinking about the potential catalyst for this Peyronies condition.  I am certain there is a relationship.

My question to you is:  Should I consult with a rheumatologist about the TNF-Alpha therapy that you alluded to, as a possible treatment for the Peyronies???  If an increase in this cytokine is indeed responsible for the PD, as some new research suggests....might there be a way to mitigate this ongoing imbalance in TNF-Alpha???

Your comments above really 'turned on a light bulb' for me.  I would bet quite a large sum that my cytokine levels are grossly out of whack since treatment, just by the numerous autoimmune like sx that I seem to display.

Thanks for any thoughts you might have on this possibly related issue!!

DoubleDose

[Hepatitis Researcher]

To the questions;
In general terms, what are the known clinical consequences of patients w/ similar such long-term conditions (i.e. - chronic over-stimulation)?

-  Increases in autoimmune concerns?

Very likely in some SVR, but the individual variability precludes definite conclusions for any particular patient:

1. Remnant HCV ("PseudoHCV, since most will be crippled mutants") will vary widely in amount.

2. Innate response to this remnant amount will vary and the types of remnant will matter as well.

3. Any increased innate stimulation that persists is typically followed by counter-regulative measures "immunosuppressive regulatory machanisms' if you will, that are just as complex as the activations of the defense machinery and badly needed for the stability of the organism. Thus the degree of these "response suppressive" mechanisms is itself genetically variable and typically starts to deteriorate with age, that is among the reasons why so many older people are chronically inflamed.
Thus some counterbalance their HCV remnant induced cytokine elevations fairly well and feel good, others suffer dearly.




-  A lowered or lessened ability of the immune system to properly respond when called upon to do so?

Chronic innate induced inflammation is both a call to action for the immune system as well as a reason for exhaustion and chronic molecular damage to the delicate machinery needed to properly and optimally operate the adaptive immune responses. Thus a decrease for example in Bcell diversity can be caused by chronic inflammation.
This is however a very broad concept. For example myocardial fatigue and insufficiency/failure can be hastened/caused by chronic Gingivitis/Periodontitis, because the inflammatory signals sent out body-wide activate the hidden defense system/eg TNFalpha production of the cardiomyocytes themselves, causing long term molecular damage to the contraction machinery. Similar mechanisms are likely at play in the immune system, but much harder to separate in the setting of ever variable activity.

-  Would it be a reasonable assumption that in this particular type of chronic immune response (to occult Hep C) a fibrotic response would not be unusual?
NOT LIKELY, SINCE THE FIBROTIC RESPONSE REQUIRES A FAIRLY STRONG LIVER SPECIFIC INNATE RESPONSE.

Again the actual degree of a system-wide cytokine level elevation caused by HCV remnant stimulation as described in that paper would need to be investigated in each individual by cytokine level measurements, serially, since these tend to fluctuate. Unfortunately these tests are not yet well standardized and the prime example, TNF alpha, is not even typically used by rheumatologists to test their patients before initiating anti TNF alpha therapy - which is used in increasing numbers lately for various immune mediated disorders.