F3s and F4s - how sure are you?

[willing]

What led you to believe your F3/F4 diagnosis - specifically how much correlation did you see between different indicators/predictors?

[willing]

hey - sounds good - we can compare photos! I tried to get my kids interested in my colonoscopy pics but to no avail. The FS was with HR so I have his assessment of the quality of the readings - but beyond the stiffness measurement I don't believe any anatomical/cellular info is provided, unlike  us/bx/scopes.

I'll ping Senora Frijole - thanks - and stay well, just one more hot summer to go and by the fall the world will be looking a whole lot better!

[Bill1954]

Willing-

I’ll have results to share from an upcoming endoscopy next month; I’ll try to drop you a note FYI. Actually, he’s doing a colonoscopy and endoscopy in the same visit; I figure you’re current interest lies in the northern hemisphere right now, so I’ll limit the geography in my account. And yes, I asked the doc to make sure he sequences the ‘scopes properly; I told him if I woke up with halitosis, I’d never forgive him.

Was there any narrative report along with the quantitative results of the Fibroscan that might aid in your decision?

I believe Frijole (Kathy) had a laparoscopic Bx performed recently… if I bump into her, I’ll give her a nudge toward this thread so she can add her thoughts to the pile. You might want to drop her a note as well.

Again, best of luck regarding you’re upcoming decisions… I’m not sure what to add given your voluminous knowledge of this process already.

Take real good care, my friend—

Bill

[willing]

yes,  I agree that a reduction that large seemed  just too good to believe, hence the follow-up fibrosure and recent fibroscan which led to my current pickle.  On the other hand, the sampling accuracy of bx's, within a stage at most, seems widely accepted and is one of the underpinnings of liver treatment, eg
http://www.medscape.com/viewarticle/474410

My US results from today were spleen diameter 11.2 cm,  about the same as previous scans in which it was measured, and portal vein 1.3 cm with an overall read of 'normal appearance' . I'm starting to hold out hope that the FS is the unrepresentative marker .. though from what I understand of its operation that seems most unlikely.

[JennyPenny]

"First, on re-reading your biopsy/Fibroscan  results, one reasonable theory is that all of the readings are correct, but that you had a significant (but temporary) regression of fibrosis after each of your treatments. This seems consistent which what I've read and heard."

I'd think it was more likely a smapling error rather than fibrosis reduction. The HALT C studies have shown that people with Stage 4, with an SVR of over 5 years, only have a 20% chance of fibrosis reduction. As the Stages go down, the results are better and better.

Here is how I knew I had cirrhosis:

Enlarged liver & spleen by palpation & ultrasound
Slightly elevated AFP 10-12
Slightly depressed platelets 130,000
Slightly depressed white count
All other parameters are normal. The bilirubin and albumin, etc., don't change with cirrhosis until the patients starts to decompensate.
Two biopsies gave me the same results

[willing]

hector - thanks for the update. My bxs were done in different, local hospitals. The amount of sample collected was always judged ample by the pathologists. However, this time,  I will  try to line something up with the  Drs from a transplant/research center and ask about ample needle gauge and multiple cores.

The pattern I'm seeing in the posts is that everyone got direct evidence from a bx along with some corroboration. It says something about the resilience of the liver that the biochemistry continues to look fine even as the mechanical stress of pumping  blood through accumulating collagen becomes evident.

jim: many thanks for the full-blown 'remembrance of things past' edition  - it's very helpful in understanding the landscape (and congratulations on the  9.5 to 8 shift - from where I'm looking, that looks great).

I agree that the most worrisome interpretation is that all results are accurate and I've progrssed from a 1 to a 4 in two years. If so, I should be getting my re-tx started *now* rather than sitting here typing. However, everyone above seems to have gotten direct bx evidence of their fibrosis and I'm going to risk waiting for this to come in before committing.

The lap is just a guess my part at this point. I believe the quality/experience of the surgeon definitely affects the amount of tissue collected. avoidance of other organs etc, but I don't see any way it can contribute to whether the tissue is collected  from a region that does/does not give evidence of fibrosis. This would require guiding a bx with visualization along the lines of the fibroct imaging mike posted about recently and as far as I know this is not available, so I'm wondering whether a laparoscopic approach might work.

The trouble is going to be convincing them to do another bx given that the last one was only two years ago, there isn't yet any other evidence, and fibroscan is not yet standard here. If I do retx soon, I'll probably go with ntz and hope tela/boce get approval in time to add them to the tail-end. As I've posted before, I continue to believe  that for relapsers with reasonable ifn response, eliminating virus at the end may be worthwhile.

Hope all is well with you.

[jmjm530]

Will: however, your simmering may have reduced the details a bit too much.
---------------------------------------------
OK, if you don't like the Julia Child's version, here's how it plays in "H*ll's Kitchen ...

First, on re-reading your biopsy/Fibroscan  results, one reasonable theory is that all of the readings are correct, but that you had a significant (but temporary) regression of fibrosis after each of your treatments. This seems consistent which what I've read and heard.'

I'd stlll get that biopsy and hopefully it will prove this theory wrong and your '06 biopsy will rule, but I guess we're both rightly just a little skeptical of that now.  Moving ahead, and should you end up treating, have you considered trying to get into a Telaprevir trial for prior non-responders? As you know, I'm not a big fan of SOC these days and some of the question marks raised on Telaprevir/prev non-responders should be answered very soon. And before I forget, have you read about the statin/viral load connection. Might be a good time to start statins and certainly enough other reasons for many of us.

As to your direct  question, "What led you to believe your F3/F4 diagnosis"...

Like many here -- and unlike yourself at this point -- I had almost no knowledge about Hepatitis C prior to treatment. For that reason, I relied almost exclusively on the results of my multiple biopsies over the years as explained to me by my liver specialists. I didn't probe deeper because I didn't have the knowledge to probe.

My last biopsy -- about three years before I started treating -- read grade 4, stage 3/4, which I was explained put me somewhere between stage 3 and stage 4. I planned on treating soon thereafter but one thing or another delayed treatment for 3 years.

During the first month of treatment, I had these same slides read again by a pathologist of an outside consult and was staged at 2. Then called the original pathologist and found out that "3/4" actually meant stage 3 out of a possible 4 stages and not between stage 3 and 4. Then had the slides re-read by my treatment docs's pathologist who was kind enough to spend an half hour with me and actually offered to let me look at the slides. This pathologist staged me at 2.5. A fourth reading of same slides was done by the patholoigst affiliated with the Fibroscan trials. He staged me at 3 and was to say the least not particularly happy that I tracked him down on the
phone :)

Throwing out the original misintepretation -- between stage 3 and 4 -- which prompted me to treat (probably would not have treated if told I was a stage 3) -- the readings therefore ranged from 2 to 3. Still, as explained to me by one doctor and by the pathologist who was overly generous with his time, the crux of the matter was in the wording of the report,  and not the numbers. This is very important to understand because two reports can end up quite similar in description/observation but still a stage off. Therefore, a good read and understanding of the report can tend to bridge (some pun intended) some of the discrepencies found in staging of identical slides by different pathologists.

In my case -- and I believe this is somewhat typical -- the difference in staging had to do with the extent or "read' of the bridging. One pathologist saw it as being complete and gave me a "3", another saw it as incomplete and gave me a "2'. The pathologist who took his time with me (and my guess also took his time analyzing the bridging initially) said it was somewhere between complete and incomplete and therefore a "2.5", but technically it was a "2" if forced to choose which one it was closer to. This is consistent with my first Fibroscan taken 3 months into treament with kpa of 9.5. A later Fibroscan taken 4 months post treatment showed a kpa of 8 which is consistent with  a beginning stage 2.

To the markers you list before I knew any of the above...

1. out of range results on individual tests (eg high  bilirubin, alpha-fetoprotein or creatine, low albumin or platelets, etc.)
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I would have to go back many years (if I still have the labs) and check platelets, but the other markers were all normal. Platelets in the few years prior to treatment were in the 170 range and still are.


3) blood-based markers like Fibrospect/Fibrotest that improve on (2) by measuring additional levels
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Wasn't aware of these tests at the time, but fond out later my tx doc doesn't use or have much faith in them. YMMV.

4) detection of enlarged spleen (splenomegaly) or portal vein diameter on ultrasound as indicators of portal hypertension (PH) (what diameter is considered out of range?)
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With my very limited knowlege pre-tx, I did ask about 'splenomegaly" which was noted on several pre-tx ultrasounds. The explanation given by my doc was that this was not unexpected given my history and not to worry. No mention of cirrhosis. I'll have to check back on the portal vein diameter, etc,.

5) palpable edge of liver and/or spleen tip on examination

Very early in the game -- 30-40 years ago, I do believe my liver was palpable along with some sort of sensation. It was not palpable, nor was their any sensation, for at least the ten years prior to treatment.

6) detection of varices/ascites on endoscopy

A colonsocophy prior to tx and ultrasounds found no ascites. Endoscophies were done during and after tx and showed no varices although it did pick up Barrett's.

7) transient elastography/fibroscan readings of 12-14 and above

(Already discussed)

8) good-old trichrome stain on bx tissue - the "gold standard"

(Already discussed).
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That's it, from Hell's Kitchen...

BTW you mention a lap biopsy, wondering why so invasive? Personally, I'd just go to a major teaching center and have it done by whoever is the "go-to" biopsy person there. Some fellows have done hundreds (or more) and really have it down. None of my biopsies were guided, but except for the first, were all done by "go-to" guys and they were over in an instant with good samples taken each time. I'd still prefer this route to a "guided" biopsy by someone that has only done a handful, but maybe times they are a changin' -- haven't really looked into biopsies lately, nor do I intend to.

All the best with your upcoming decisions.

-- Jim

[HectorSF]

Here's why I'm asking:
- first bx '92: early bridging/cirrhosis
- biopsy '00: stage 2
- biopsy '06: stage 1 ( slides examined by two independent pairs of pathologists)
- fibrospect '07: 72 (only 10% probability of an F1 getting such a high score)
- fibroscan '08: 12.4 - consistent with a F3/F4

Sorry you are going through "the maze as it were". This does look like a nightmare to figure out. I assume these were done at different hopitals? I agree with "Standard/mainstream indicators of advanced fibrosis/cirrhosis" mentioned.

I have cirrhosis. Only discovered after 38 years of having HCV and HBV with normal blood tests. I felt healthy and good to. Had been to doctor for blood tests in maybe 1 year. My platelets were low. I forget exactly maybe 90,000. My AST was slightly above normal. My GI puts his hand on my right chest. He said "Enlarged spleen". From there on cirrhosis was confirmed by biopsy. I guess I was lucky to have it figured out so easily! Gee, I guess there is an upside to my cirrhosis!

Cirrhosis (scar tissue in the liver) causes portal hypertension (high pressure in the portal vein)....
Portal hypertension cause the spleen to enlarge....
An enlarged spleen traps platelets. (The platelet count begins to DROP)....
A low platelet count causes blood to not clot properly. (Blood takes longer to clot.)
(As the platelet count drops, The Prothrombin Time begins to RISE)....
A high Prothrombin Time causes a high INR
(So as cirrhosis advances (over time)...... the platelet count falls lower and lower, the PT and INR rise higher and higher.)


Hector

[willing]

gauf: thanks - did the spleen enlargement show up on both us and endoscopy ? One useful hint I picked up from HR was to always ask for spleen/portal-vein diameters while lying there with the jello on your stomach. While the relevant anatomy is being visualized, getting the dimensions only involves a couple of mouse clicks. The  report however, may only include language like "appears normal" which doesn't help later scan-to-scan comparisons.

jim: wow, i'm thoroughly impressed  - I've never been able to get any to talk to me... however, your simmering may have reduced the details a bit too much. I suppose if I had a stage 3 bx in hand I probably wouldn't be worrying further but in its absence I'm wondering how likely it is that there could be no "corroborating evidence" - were you aware of any other indicators that supported the bx staging?

bill: many thanks for the detailed summary. Whatever reservations I have about soc will quickly evaporate if the 3-4 status is confirmed. You gotta do what you gotta do and when the time comes you and mikesimon will be my role models for how to persevere through hardship. I hope all is well with you.

I agree with your skepticism about the reliability of the biochem markers. One of the few advantages of a chronic illness is that one builds up quite a stash of medical records. I dug out some of the old musty boxes and will pore through looking for trends but on first impression there is a remarkable amount of variation.

On the other hand, both trichrome stain and the stiffness measured by the FS wave are pretty unequivocal . I'm having an US  Thurs., an endoscopy within the month and will try to persuade the hepatologist to OK a  laparoscopic bx. hopefully a consistent pattern will emerge...

[jmjm530]

Bill: Contrary to Jim’s experience, my discussion with the pathologist that provided the report, as well as my GI doc at the time, both independently stated that this was to be considered late stage 3, early stage 4- not stage 3 of a possible 4 stages.
--------------------------------------------------------------------------------------------------------
Don't want to put words into your doctor's mouth, but is it possible that the notation meant both stage 3 out of a possible 4 stages, but that also they felt you were also a late stage 3?

I say this because the traditional way of staging is to use a whole number, and let the wording of the biopy report define where one might fall within that stage. That's why you often don't see stage "2.5" on a biopsy report, although one of my pathologists did stage that way.

But regardless, the important thing regarding what "stage 3/4" (or any notation) means is to find out what the person who made the notation -- the pathologist in this instance -- meant it to mean. The fact that one pathologist might mean one thing and another pathologist another -- doesn't surprise me in the least. For that reason, I made it a point of getting the pathologist on the phone -- all five of them at one time or another :) -- to find out what their take was. No great surprise to find out that it sometimes differed in some degree from what the doctor told me. BTW getting pathologists on the phone is sometimes not the easiest thing unless you're an MD.

-- Jim

-- Jim

[Bill1954]

Hi Willing;

Boy, your history reads like a pathologist’s nightmare/don’t-let-this-happen-to-you-scenario. Difficult to find any trend there, isn’t it? No wonder you’re looking for further guidance of some sort. Were there any narrative comments provided along with the quantitative results of the Fibroscan to direct you? You’ve expressed previously how you feel about SOC treatment; I’m sorry to hear it’s come down to this.

To answer your question;

Biopsy in Feb ’05 grade 3, stage 3/4. Contrary to Jim’s experience, my discussion with the pathologist that provided the report, as well as my GI doc at the time, both independently stated that this was to be considered late stage 3, early stage 4- not stage 3 of a possible 4 stages.

A U/S scan prior to biopsy reveled Hepatosplenomegaly (spleen 16.1 x 5.1 cm), along with a narrative notation that there was an increased echogenicity and coarsening of texture.

Hepatic margin was palpable and firm by my GI as well as PCP docs.

A recent (12/07) *in treatment* Fibrosure result of .92.

However, biochemical markers are OK; platelets around 200, avg. t. bilirubin 1.2, avg. INR 1.0; all suggest near-full synthetic capacity.

Am I stage 3/4 or >? Probably; however, the lack of support from biochemical markers is inconsistent with cirrhosis, I believe. Based on my doctor’s suggestions, along with what I’ve been able to piece together myself, suggests I should be treating aggressively with whatever protocol is currently available.

I feel for you, bro- as Jim mentioned, an additional biopsy is probably warranted at this point for decision power.

Let us know what you decide, and take good care—

Bill

[jmjm530]

Will: What have people observed and how sure are you of your  F3/F4 diagnosis?
--------------------------------------------------------------------------------------------
I was diagnosed as stage 3/4 prior to treatment. BTW that notation means stage 3 out of 4 possible stages and not between stage 3 and 4 as I was initially led to believe.

The long answer to your question is really too long, but to simmer it down I don't believe that you can rely on many of the outside markers you list --  as it's hard enough sometimes just getting a bead with needle biopsy and Fibroscan as I think you're finding out.

Personally, if my treatment decisions were based on stage -- as yours appear to be and as mine were -- and if I had an '06 biopsy that showed stage 1 versus an '08 scan that showed F3/F4 -- then I would no doubt get a current biopsy to help me with any treatment decision. Of course, my bias was (and still is) to treat only as a sort of last resort, and therefore I would want to be as sure as possible before plunging in, especially with SOC drugs.

[gauf]

Biopsy in '05 Stage 2/3.  Downgraded to stage 4/1 due to 2 failed toxes as well as detection of enlarged spleen, portal hypertension, low platelets, and varices.

[willing]

Standard/mainstream indicators of advanced fibrosis/cirrhosis seem to include:

1) out of range results on individual tests (eg high  bilirubin, alpha-fetoprotein or creatine, low albumin or platelets, etc.)
http://www.cumc.columbia.edu/dept/gi/labtests.html

2) weighted combinations of the above, optimized to distinguish advanced fibrosis (eg the Lok formula, or
http://www.haltctrial.org/cirrhosis.html

3) blood-based markers like Fibrospect/Fibrotest that improve on (2) by measuring additional levels

4) detection of enlarged spleen (splenomegaly) or portal vein diameter on ultrasound as indicators of portal hypertension (PH) (what diameter is considered out of range?)

5) palpable edge of liver and/or spleen tip on examination

6) detection of varices/ascites on endoscopy

7) transient elastography/fibroscan readings of 12-14 and above

8) good-old trichrome stain on bx tissue - the "gold standard"


Here's why I'm asking:
- first bx '92: early bridging/cirrhosis
- biopsy '00: stage 2
- biopsy '06: stage 1 ( slides examined by two independent pairs of pathologists)
- fibrospect '07: 72 (only 10% probability of an F1 getting such a high score)
- fibroscan '08: 12.4 - consistent with a F3/F4

Meanwhile, I failed 6 months of monotherapy back in '93 and relapsed on a standard 48 week soc in '03.

Based on my last bx I was prepared to wait 6 years or so for a tx that combined polymerase/protease inhibitors. All other indicators give no clue of advanced fibrosis. Platelets at 143 are just below normal, but they've been as low as 120 in years past and bounced back up.

However, based on my recent fibroscan - I should be getting ready to re-tx within the year.

My GI was clear that you don't get to F3/F4, even though possibly still asymptomatic,  without corroborating evidence, particularly some signs of portal hypetersion. What have people observed and how sure are you of your  F3/F4 diagnosis?