Reversibility of Hepatic Fibrosis and Cirrhosis--Is it all Hype?

[mikesimon]

"Now that the idea that hepatic fibrosis is reversible is taking root, many clinicians are beginning to ask why, if fibrosis is reversible, is there so little progress in the clinical setting, and will patients ever really benefit from antifibrotic therapies? Underlying such questions is a subtle cynicism that the reversibility of fibrosis and cirrhosis has been overhyped

[revenire_1]

I went from stage 3 to stage 2 (yes, I know biopsies can be off a grade) but there have been others here that have done the same or better: BobK for one.

[saliier]

It is now overwhelmingly confirmed in multiple well documented studies of patients with cirrhosis from different causes (Hep C, Hep B, Haemochromatosis, Acohol related liver disease etc etc) that IN SOME PEOPLE severe liver damage up to and including established cirrhosis will revert towards (and in some well documented cases back to) normality given sufficient time AND removal of the underlying injurious agent (i.e. clearance of virus, stopping alcohol and de-ironing the liver).  There is hope for all.

[jmjm530]

Really two discussions going on here and partly due to what I think is the confusing nature of the article, at least to me.

The confusion is that the article is combining thoughts by the author on anti-fibrotic drugs other than SOC while at the same time talking about how SOC can reverse fibrosis, the latter of which most of us here talk about often in terms of our own treatment. Again, from the SOC point of view, this article is 100% positive regardless of what I consider to be a misleading headline.

Saw my liver specialist the other day and he reinterated that if not already, in the not to distant future I should be seeing a one or two stage regression from SOC.

In fact, when we talked about statins, niancin, alcohol and other substances that might tax the liver, he again reinterated that I should no longer be viewing my liver as abnormal. This same thought was echoed by another liver specialist I consulted with right after SVR. His point being that there are certain things -- mentioned above -- that tax the liver but the fact that I am now SVR does not mean I have to take any special precautions. And just so there's no confusion, this does not mean I've been given carte blanche to abuse my liver, just that whatever cautions I might take would be similar to prudent cautions that should be taken by someone who never had HCV. In fact, I was encouraged to have a glass of wine 4-5 times a week to raise my HDL cholesterol which at this point is a much more important health concern than my liver. This latter statment has been confirmed by both my cardiologist and hepatologist.

Probably also best to add before this gets quoted out of context and somehow turned into my "recommendation" that this is what they told ME because of MY case history (pre-tx stage 3 with no other symptons/indications of liver damage) and may not apply to others, regardless of their stage.

All in all, I found that very encouraging as well as all (including this article) that has been written about SOC and fibrotic progression. The acid test of course will be a peek into my liver itself which hopefully I will be doing at on some sort of basis in the not too distant future  as I'm told that the Fibroscan device will soon start appearing in many centers throughout the country.

-- Jim

[APKhaos]

Jim's post, among others in this thread, sums it up nicely. The evidence is building to the point that regression is becoming accepted as an outcome of successful SVR for HBC & HCV patients.

I've had some interesting talks with the folks at the trial center, which is part of a large Liver Disease clinic in a DC area teaching hospital. It was surprising to hear that this is a dramatic change in the conventional thinking of just two to three years ago. Regression was not generally though to occur where fibrosis had progressed to Stage 3 or later. It now turns out that stage 3 cases have been shown to regress dramatically. I suspect that portal hypertension and related effects of cirrhosis are complicating factors. The studies I've seen tent to focus on pre-cirrhotic fibrosis.

Its good news, and welcome news.

[mikesimon]

I didn't expect to see any studies anyway.

[mikesimon]

Sulfasalazine - Covered it? Okay then, if you say so.

[Kalio1]

I think Dominic's post covers it nicely. Im too sick to do research.


thanks a lot for posting this info Dominic.

[EspritLibre1]

Thank you.  Great article, encouraging.  Hope you're well, enjoy your posts.

[mikesimon]

The conclusion stated in the article you cited is:

Conclusion: Sulfasalazine is a potent inhibitor of GCDCA induced hepatocyte apoptosis in vitro and in the intact liver.

Maybe you can see a connection between this conclusion and Sulfasalazine's potential to reverse fibrosis but I can't. I have searched for studies and articles on Sulfasalazine and I can find nothing regarding liver fibrosis other than rat studies - no human studies. I find material on Sulfasalazine and pulmonary function, RA and a few other diseases but nothing about human livers. I would appreciate you posting what you have because this subject interests me greatly.

Mike

[Kalio1]

I agree that drug therapies we hear of are too often spun and reduced to a sound bite making it appear there is a simple answer. I agree that this harms people rather than helps them. While it might service "big pharma" to instigate interest in products, it is not helpful to lead people to believe an easy solution is at hand.

However, with less than a minute devoted to researching  the subject ( a subject I looked into intensely last year , I found this indicating positve effects on intact human livers:

http://gut.bmj.com/cgi/content/abstract/55/5/719?rss=1

and I know I have a number of other studies filed somewhere showing promise using sulfasalazine in humans to reduce liver inflammation/fibrosis including a study that was done on alcoholics that had dramatic results, even in those that were still drinking believe it or not...

While it is important for patients not to be sucked into the "spin" of possible solutions to these issues, it is also important to inform people of the promising solutions that are discovered particularly in a case like sulfasalazine which is an existing drug with tons of studies and research under it's belt having already been done ( it is used for other ailments currently and has been for years), it also is FDA approved and available. It is relatively affordable to boot.( compared to pegintron!) The jury is still out on it's impact on liver fibrosis but it definately warrantsattention and more study and looks very promising. With the situation as it is, with not nearly enough replacement livers to go around, a solution that is already on the market and has little to no side effects is a big plus.

It is no "magic bullet" but it is not true that "only one study on rats" is the basis for the optimism.

To say that like this author of the article does is just spin of a different color.

[GoofyDad]

I read that. My BX report also goes into a discussion about various architectural attributes and whenther or nor they supprt a cirrhosis diagnosis. I've always felt since reading it that, like pies and BMs, there's more to cirrhosis than the crust and the filling.

[andiamo]

My doctor thinks that if portal hypertension develops, it is not reversible, since the blood flow through the liver is inadequate for re-growth.

[Tallahassee]

I think the Infergen trial is a good option. Go for it, if you can.

I'm also a non-responder to Interferon, but on Infergen I'm always UND, even though I did not have yet a sustained viral response.  I never reversed my fibrosis either, but I hope that may be Infergen slowed the fibrosis progression. If you care for the details, you may see my treatment history on the "roll call" tread by illo posted on 5/17or 5/18?

What I was thinking later...  For people like us (non-responders to regular interferon) Vertex treatment may be not a very promising option, since it seems relies on Interferon's power to fight mutated viruses.
It may be the best option for us to have Vertex (+ other polymerase/ protease inhibitors) with Infergen (or a combination of interferons). Also, it will be helpful, if they manufacture a pegalated infergen version.

I'm sorry for the Diabetes... It is hard to get rid of this bug (or rather RNA :)) without acquiring different side effects... unfortunately.

But anyway, I'm refusing to be negative!! :)
Have a wonderful day & holidays! (and for all members of the "club"!)

[BThompson4]

My transplanted liver went from F2 fibrosis one year prior to beginning SOC to "no significant fibrosis" (zero to F1) in a biopsy done during week 36 of treatment.  My hepatologist said to today that can happen but that biopsies can be unreliable in that they are small samples of your liver and that there could be areas of greater damage in the liver that were not sampled.  Biopsies can be unreliable.

[Dominic777]

Presented at the 2007 Digestive Disease Week (DDW) Meeting, May 19-24, 2007; Washington, DC.
This study was supported by Roche Laboratories.

Paul J. Pockros, MD1; Paul Martin, MD2; Ellen Lentz, PhD3; Fayez M. Hamzeh, MD, PhD3; and Anna Lok, MD, FRCP4
1Scripps Clinic, La Jolla, CA, USA; 2Mount Sinai School of Medicine, New York, NY, USA; 3Roche Laboratories, Nutley, NJ, USA; M1854 4University of Michigan Health System, Ann Arbor, MI, USA

"....Improvement in activity and/or fibrosis score was observed in 93 (86%) of 108 patients who achieved SVR, and in 45 (44%) of 103 patients who did not (P<.001).... Of those not achieving an SVR, 50% receiving 48 weeks vs 29% receiving 24 weeks therapy achieved 1 or more grade improvements in fibrosis or inflammation (staging and grading) (p=.049)...."

Introduction
Current treatment practice in HCV, aimed at achieving sustained virologic response (SVR), is to discontinue treatment in patients with detectable serum HCV RNA at 24 weeks.

Improvement in inflammation has been reported in patients with HCV who achieved SVR after receiving interferon with or without ribavirin, and in a smaller percentage of patients who failed to achieve SVR, suggesting that interferon has a direct effect on liver histology.1-4

Longer treatment duration may enhance histologic improvement regardless of SVR.

Study Objective
To determine if treatment of HCV genotype 1-infected patients with peginterferon alfa-2a plus ribavirin for 48 weeks is associated with a greater degree of histologic improvement than treatment for 24 weeks.

Author Conclusions
Among patients chronically infected with HCV genotype 1, those who achieved SVR after treatment with peginterferon alfa-2a plus ribavirin were more likely to have histologic improvement than those who did not.

The complete article:
http://www.natap.org/

[jmjm530]

For those not registered with MedScape, or otherwise did not read the complete article, the first paragraph quoted can be quite misleading as the article in its entirety is acutually quite positive.

First, the author acknowledges fibrotic reversal in SVRs which is the reason many of us treat. He writes: "...First of all, progress has been tremendous. The mere idea that fibrosis can regress when the initial disease is controlled or cured is exciting, given the decades of dogma that suggested scar formation was a unidirectional pathway. Ample evidence that fibrosis regresses with control of hepatitis B, hepatitis C, or other chronic liver diseases[2] attests to the tremendous regenerative power of the liver, and the rapid progress made in the development of targeted antiviral and disease-specific treatments..."

And the conclusion is equally postive, as the author says: "...So, hindsight indeed provides ample evidence of gratifying progress in hepatic fibrosis. Continued evolutionary development that changes our thinking about fibrotic liver disease and its prognosis is likely in the future. Revolutionary advances would certainly be welcome, but slow and steady gains should still justify hope without provoking hype..."

What the author appears to be saying is that while there may be some hype in this area, bottom line is that SVR has been shown to reverse Fibrosis and there have been "slow and steady" gains in other areas as well.

So to answer the author's own question as presented -- Is the reversiblity of hepatitic fibrosis and cirrhosis all hype? The answer is clearly no.

-- Jim

[mikesimon]

The article addresses the fact that not all cirrhosis is necessarily the same.

"This observation raises another challenging paradigm shift brought about by the growing evidence of fibrosis regression, namely that not all cirrhosis is the same; in fact, patients with cirrhosis can experience a widely variable clinical course. Our current staging methods do not, however, discriminate sufficiently between different degrees of cirrhosis. This oversight is understandable because until the past decade it hardly mattered whether a patient had 'early' or 'late' cirrhosis

[GoofyDad]

My hepatology transplant center certainly recognizes regression in cirrhotics as a potential outcome. They look at a 5 year timeframe for progress - not overnight. I asked why it took so long to recognize this and the responded it's because SVR is relatively new, SVR in cirrhotics, newer, and in other populations like alcoholics - the assault on the liver often was ongoing. In my case they gave me 50% odds of 2 stage regression over the long term.    

[GrandOak]

I read somewhere the same information, but I don't know the "second" regenerating organ. Is it skin?

I think so, but there could be another internal one, I'm not sure at the moment.

How are you doing?

Hanging in there and in the monitoring stage of the diabetes which I've developed post-tx.  Sounds like pills are out as treatment for that given abnormal LFT's as a result of HCV still hanging around.


Do you have a direction for your future treatments?

I'm not sure, I've been told there are no other options besides waiting for new meds and seeing if they might provide another chance at treating.  Sounds like specialists here are not in favor of multiple tx attempts.  So in the meantime I'm getting regular AFP and  ultrasound tests.  Although I'm now scheduled for an endoscopy and MRI in a couple of weeks to consider whether banding is necessary and to get a more precise view of liver than ultrasound provides.

I am looking into an Infergen trial just starting for patients who showed some response during tx but did not clear.  Sounds like the Mayo here in MN may be a trial site and I'm looking to get contact information for it. Here's the trial link:

http://www.clinicaltrials.gov/ct/show/NCT00456248?order=7

Did you consider a maintenance therapy?

I was told that maintenance was not an option either.  Perhaps something to due with the fact that my ANC and Hgb battles were areas I got hit hardest with during tx.  It's not really clear.

Other than that I get pushing in and pressing on taking it one day at a time.

[mikesimon]

I wasn't asking the question - that is the title of the article. The author states: "Ample evidence that fibrosis regresses with control of hepatitis B, hepatitis C, or other chronic liver diseases". Mike

[willows]

I do not believe it is hype at all, for two reasons.  The University of Washington is doing the HALT - C trial and has extended the trial, which is low dose maintenance and how much fibrosis is reversed.  Now, whether the damage of cirhossis can be reveresed, I do not know.  But my doc is from the University of Washington and has expressed to me that they are having good results from the trial.  

Whether or not a person's liver is in a stage that would warrant the treatment of low dose is another decision.  My doc wanted to wait until the trials were finished, but I have a liver bx next Wednesday (and I am really looking forward to that, let me tell you), and when we get results, he has given me some options.  Wait for teleprevir, which he is very excited about, try retreating again with the whole nine yards of poison, or try maintenance to keep me in the best shape possible for the FDA approval of teleprevir.  

We had Miles Keaton post here about 6 months ago, he is an author and big HCV advocate, a sufferer himself and after about two years of trying double dose IFN, Zadaxin and some other rat poisons, he posted here, in a stunned state, that his newest biopsy showed he had regressed two stages.  

So, no I do not think it is hype, but still such a new idea with no proven results yet, that I think it is an individual issue.  Soon, I think it will be accepted as fact, but then, to do low dose IFN for a year or two, who among us can even accept the idea?  Two years of IFN?  At best, I think it will become a stopgap measure for someone like me to keep from going into stage 4 until teleprevir or some other PI to be approved.  At least I hope so!

Willow wants maintenance

[Tallahassee]

GO:  "I don't have the studies at my fingertips, but I recall reading something on reversibility on Fibrosis being observed due to the live being one of two organs with ability to regenerate."
------------------------------------------------------------

I read somewhere the same information, but I don't know the "second" regenerating organ.  Is it skin?

How are you doing?
Do you have a direction for your future treatments?

Did you consider a maintenance therapy?

Be well

[GrandOak]

I have heard of cases were Fibrosis damage was reveresed and claims that even Cirrhosis damage was repaired, albeit the claims of the latter are almost nil when compared to those of the former.

I don't have the studies at my fingertips, but I recall reading something on reversibility on Fibrosis being observed due to the live being one of two organs with ability to regenerate.

Many medical professionals I've talked with seem to have differing opinions when Fibrosis is discussed with some believing it can go into remission and others that the damage can be reversed.

However, all have been consistent on Cirrhosis and doubt even the claim of it going into full remission.  Slowed perhaps to the degree that HCC does not develop prior to the patient passing on from other causes.  But none have noted or seen documentation on absolutely no advancement.

[r4c7]

I understand capase inhibitors are currently in early clinical trials and have shown some beneficial effect on hepatic fibrosis.  The other, perhaps more promising therapy, is gene therapy, which just might turn out to be the ultimate long-term remedy for treating hepatitis c as a whole.

But for now, the name-of-the-game is to try and get cured by the current FDA approved drugs, and give your liver a well-deserved break in the process.