Higher HCC risk with increased insulin resistance

Just FYI - if you have IR you might want to also keep on top of this one too.

Better safe than sorry....I don't want to be the harbinger of doom but I know IR is a problem for some folks around here. I hate HCC if you can't tell.....no more of my friends should die of this.

--------------------------------------

Higher HCC risk with increased insulin resistance in hepatitis C patients
May 12, 2010

Recent studies have demonstrated that type 2 diabetes mellitus (DM) is associated with high risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Insulin resistance (IR), which correlates inversely with circulating adiponectin concentration, is a consistent finding in patients with type 2 DM. Chronic hepatitis C virus (HCV) infection has been reported to be associated with increased IR. Recent studies suggest that IR plays a crucial role in fibrosis progression, and has been demonstrated to have a negative impact on treatment responses to antiviral therapy in patients with chronic hepatitis C.


A research article to be published on May 14, 2010 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Hung from Kaohsiung Chang Gung Memorial Hospital prospectively investigated the IR assessed by the homeostasis model (HOMA-IR) and serum adiponectin level in two independent cohorts of consecutive newly diagnosed HCC patients and those with different clinical stages of chronic HCV infection.

Among 165 HCC patients, type 2 DM was more prevalent in HCV subjects compared to hepatitis B virus (HBV) or non-HBV, non-HCV cases. HOMA-IR was higher in HCC patients with HCV than in those with HBV infection. In 188 patients with chronic hepatitis C, HCC subjects had higher blood sugar, insulin level and HOMA-IR than those with chronic hepatitis and advanced fibrosis.

Based on stepwise logistic regression analysis, HOMA-IR was one of the independent factors associated with HCC development. This result was similar even if the diabetic subjects were excluded for analysis. The research team concluded that increased IR, regardless of the presence of diabetes, is significantly associated with HCC development in patients with chronic HCV infection.

These findings may have important prognostic and therapeutic implications in the management of chronic HCV-infected patients. Since IR is a potentially modifiable factor, therapeutic intervention aimed at decreasing IR may be warranted in these patients.

More information: Hung CH, Wang JH, Hu TH, Chen CH, Chang KC, Yen YH, Kuo YH, Tsai MC, Lu SN, Lee CM. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J Gastroenterol 2010; 16(18): 2265-2271 http://www.wjgnet.com/1007-9327/full/v16/i18/2265.htm

Provided by World Journal of Gastroenterology (news : web)

http://www.physorg.com/news192880615.html

[Trinity4]

Interesting read and likely IR could apply to me.  That is one of the things I'll have checked out before treating again.

[jusjames]

its worth checking even for skinny people ,

[nygirl7]

Right now it's like the one darn thing that doesn't apply to me but I am going to keep my eye on it in the future because everything else seems to be going kerplonk now that I"m uh over 20.

[susan400]

My A1C's for the past year have ALWAYS been normal.  So, with that in mind, even though I've had a few blood sugars that were just barely over the cuttoff..., like 106, 102, 105,101..., my doctor is not calling me a diabetic, or even a pre-diabetic since he says the gold standard is the A1C and mine is always excellent on that front.  He's run this A1C over and over and over again, (I think he thinks if he runs it often enough that he's going to be able to call me diabetic, LOL).  NOT!  I asked him specifically, do I need to have a fasting GTT and he said no because he wouldn't change anything treatment-wise on what he'd do with me.  He said if I had an abnormal fasting GTT that the next normal step is always an A1C and since mine is always normal, that there's no reason to run a fasting GTT..., he says that would be a waste of my time and a waste of money.  This guy is an internal medicine doctor, so I am pretty sure that he knows his stuff.  Also, I might add that he's in the same group as my hepatologist and they have access to each other's records on the computer and actually talk to each other.  So, I'm fairly confident that I don't have IR.  I do thank you though, for publishing this fact.  It is something to keep in mind.

Take care, Susan400

[Cory255]

I agree, you should get this checked out.  

As far as I know, fasting insulin and fasting blood sugar can be done with the same test and ordered by any Doctor.  

It is recommeded to change your lifestyle by exercising and eating right first.

[bandman54]

I am skinny an have IR.

A1c is normal

You need to find a Homa caculator.
Have your fasting glucose and fasting insulin
tested and then calculate your Homa.
I am sure someone here can post the
formula , if not I will post later.

I your glucose is nearly always over 100
there is a chance you are IR

I finally got my glucose under 100 but insulin
is 16. So homa score is 3.34

too high!

Bandman

[Cory255]

If anything is going to increase your odds of SVR it is worth looking into...

Looks like you're about to share the HOMA equation...

Get it out in the open...  I'd like to give my teacher and scholar Co, props for sharing this equation with me.  

Get your fasting blood sugar and fasting insulin tested first.

Take your results (fasting blood sugar & fasting insulin) and multiply,,, and then divide by 22.5.  

The higher the HOMA, the more insulin resistant you are and the more SVR drops.

If you're results are less than 2... SVR 60.5%

If between 2 & 4... SVR 40%

If higher than 4... SVR 20%

[susan400]

Thanks for the info, but I'm going to just stick with what my doctor's are telling me.  I've been having to go to the doctor's too much already with upteen tests and procedures and quite frankly, I'm just sick and tired of being in the doctor's office and being stuck and scanned and poked and prodded!  Recently, I went through this whole thing with the rheumatologist running all these blood tests, having me get an MRI of my knee which has swelling and after all that expense and testing and procedures, nothing was ever able to be diagnosed in a definitive fashion.  Every 3 mon., these doctor's are having me get bloodwork and if ANYTHING even slightly abnormal comes up on them, they send me back in for even more bloodwork.  The other day, they called me up wanting me to get another bone densitometry and I told them to wait until the fall.  I don't want to go through a whole huge workup trying to have them make me diagnosed with IR, just to end up having something else for them to call me in for constantly.  No thanks.  I'll take my chances.  I already get ultrasounded or MRI's every 6 mon., if any Liver abnormality i.e. Liver CA shows up, it will be caught early.  I am not cirrhotic yet, so I'm not going to get into all this worrying.  Thanks for letting me get on my soapbox!   Susan400

[mikesimon]

Diffuse Cirrhosis-like Hepatocellular Carcinoma: A Clinically and Radiographically Undetected Variant Mimicking Cirrhosis.

Jakate S, Yabes A, Giusto D, Naini B, Lassman C, Yeh MM, Ferrell LD.

*Department of Pathology, Rush University Medical Center, Chicago, IL daggerDepartment of Pathology, University of California San Francisco Medical Center, San Francisco section signDepartment of Pathology, University of California Los Angeles Medical Center, Los Angeles, CA double daggerDepartment of Pathology, University of Pittsburgh, Pittsburgh, PA parallelDepartment of Pathology, University of Washington, Seattle, WA.
Abstract

A rare variant of hepatocellular carcinoma (HCC) is encountered that produces small cirrhosis-like nodules diffusely throughout the liver (CL-HCC), instead of a larger evident mass. This pattern remains undetected as carcinoma clinically and radiographically and is unexpectedly discovered after liver transplantation in the explanted native liver. We studied 10 such cases (9 males and 1 female, age 35 to 80 y) from 4 medical centers. The pretransplant clinical, laboratory, and radiographical studies were reviewed to determine the cause and stage of liver disease, alpha-fetoprotein (AFP) levels, and detectability of a mass on imaging. All 10 cases had underlying cirrhosis of varying etiology [3 hepatitis C virus (HCV), 3 alcoholic hepatitis, 1 hepatitis B virus, 1 autoimmune, and 2 mixed HCV/alcoholic hepatitis and hemochromatosis/HCV] and underwent orthotopic liver transplantation with no preoperative clinical suspicion of HCC. Ultrasound and/or dynamic imaging showed cirrhosis and no definite HCC. AFP levels were only mildly elevated in only 3 of 10 cases (144, 150, and 252 ng/mL). Grossly, there were innumerable (from about 20 to >1000) small CL-HCC nodules (0.2 to 0.6 cm) scattered among cirrhotic nodules. Histologically, these were well or moderately differentiated HCC, often with pseudoglandular pattern, perinodular sclerotic rims, cholestasis, frequent Mallory bodies, and small vessel invasion. In addition to the usual HCC immunophenotype, CL-HCC showed frequent ubiquitin and cytoplasmic and membranous CD10 positivity, relatively low Ki-67 proliferative index and absence of AFP immunohistochemically. CL-HCC warrants recognition as a unique HCC variant that evades pretransplant detection despite massive tumor burden, mimics cirrhotic nodules, and shows some uncommon pathologic and immunophenotypical characteristics.

http://www.ncbi.nlm.nih.gov/pubmed/20463569

[CoWriter]

"My A1C's for the past year have ALWAYS been normal."
---------------------

From "Abnormalities of Glucose Metabolism, Including Insulin Resistance" by  
Michael Dube, MD, University of Indiana and ACTG researcher


"Importance of insulin resistance: Insulin resistance is the term used when the body needs more insulin than normal to control the blood sugar. Only when the pancreas can no longer produce sufficient insulin to overcome the resistance does diabetes occur, so TESTING THE BLOOD SUGAR ALONE WILL NOT BE ENOUGH TO ESTIMATE INSULIN RESISTANCE."

"it is clear that INSULIN RESISTANCE IS UNDESIRABLE EVEN IF THE BLOOD SUGAR REMAINS RELATIVELY NORMAL (i.e. in the non-diabetic range). It causes an increase in cardiovascular disease risk and abnormalities in blood vessel function and lipid levels. Interventions that address insulin resistance all tend to improve cardiovascular risk factors.

(editorial comment: you can perform an insulin resistance test to evaluate whether or not you are developing insulin resistance, which can preceed seeing sugar elevations in the blood and diabetes. Performing the insulin resistance test is a way to perhaps identify a potential problem BEFORE sugar in your blood is elevated)."

Co
P.S.  Insulin resistance is associated with having a high viral load, lower SVR, faster fibrosis progression....and no benefit.

[susan400]

Well, I do find it rather interesting to note that whenever I have non-fasting liver labs and the glucose is in the panel ..just because.., my blood sugar is perfectly in the normal range and this is after a substantial, rather large breakfast, I might add. ( i.e., eggs, toast, cereal, fruit...),   now I'm not trying to be argumentative but, IF I was IR, one would reason that I would have an elevated blood sugar after a high carb meal?  I'm telling you that my blood sugar was like 70 after eating, toast, whole wheat cereal, egg-whites, fruit, juice, coffee....   The toast was not that cardboard tasting low-carb type, it was just normal variety whole wheat toast.  The cereal was not some type of Kashi or Oatmeal, it was Wheaties complete w/all it's added (god-forbid...little bit of sugar).   And, oh, by the way, I also eat chocolate.  However, my weight is normal for my height.  All the other markers for IR are not there.  I have normal cholesterol, normal triglycerides.  My waist size is within normal limits.  This is based on my doctor's assessment, mind you.  My thyroid is normal.  My blood pressure is normal (in fact on the low side).  So, why is it that so many on here are questioning my statement that I am not IR???  What do you expect me to do, go and stand in front of my doctor w/my hands on my hips and DEMAND that he do a fasting GTT?  There are many reasons why someone can be not clearing the virus and it doesn't always have to fall into the category of IR.  Yes, I do have some elevated blood sugar's, but they are not THAT bad and my doctor said that under to old guidelines, that we would not even be having this conversation.  It's just since they lowered the limits on the blood sugar that this has become an issue.  That's my opinion on this.  Susan400

[willing]

There's something I haven't been able to sort out about the HOMA index calculation - I'd be curious to hear any thoughts/corrections on this.

The simple formula for HOMA1 as Cory writes above is FI*FG/22.5 where FI is fasting insulin in uU/ml and FG is fasting glucose in mMol/L. If FG is reported in mg/dL, common in the US, you first have to change units by dividing by 18. So for bandman's readings, HOMA1 is
(16*(100/18))/22.5=3.94
which would be outside the normal HOMA range and indicate possible IR.

However, HOMA1 has been criticized for high variability and an updated formula, HOMA2, was introduced by the authors

Unfortunately the HOMA2 calculation is not a simple multiplication and involves a non-linear fit. Inputs are the same and it is available from the authors' site
http://www.dtu.ox.ac.uk/homacalculator/index.php
either as an executable or as an excel spreadsheet. For FG=100 mg/dL and FI=16 uU/mL the HOMA2 value is 2.1 which is  close to normal.

Reference  ranges for FG  are normal lt 100 and  FI normal lt 17  - or at least those were the ranges from my last FI/FG tests, the FI reference range may vary depending on test). So  it seems consistent that in-range FI/FG would yield in-range HOMA2.

[CoWriter]

CS created a HOMA calculator.  I'll send it to you.

Is 25 cents a fair price?  LOL  Want me to add it to your bill?

Co

[willing]

sure - put it on my tab. I'll add it to my collection of dubious bioinformatic software...

But seriously, doesn't the discrepancy seem a bit weird? This isn't just rounding error.  By one measure bandman's numbers indicate serious IR, by the other (newer) index he's very close to in-range. Which is telling the truth?

[Cory255]

Here are my test results.  My Glucose is 88 mg/dL.  My Insulin result is 9.4 uIU/mL.  According to my calculations my HOMA-IR score is 2.04.  I think I'm okay.  

[Cory255]

From what I've heard, a score less than 2 is good, and a score greater than 2 indicates Insulin Resistance.  Looks like that's where I'm headed if I don't do something about it.  Good thing I got this checked out.  

[willing]

the HOMA2 score for 88 mg/dL and 9.4 uU/ml is 1.2. (you can get the calculator for Matthew's revised index at the Oxford university link above to check).  Ranges for HOMA1, HOMA2, scores generally seem to consider lt 2 OK. Here's a Stanford paper that reports insulin/glucose/HOMA values for 490, healthy, non-diabetics. (free-access)
http://www.ncbi.nlm.nih.gov/pubmed/10868826

From Table 1, avg fasting insulin was 12 and average HOMA-IR 2.7 .

Overall,  doesn't look like IR is an issue for you.  

[IAmTheWalrus]

Great information. I was concerned about this during TX as my blood glucose was often a little elevated. Post TP I had to take insulin but glucose returned to normal whan I got off the steroids.

After TX, and subsequent relapse, I got an insulin test and computed HOMA score as 2.8. The problem is that I could not find any references to what this meant. What is too high, what is too low, etc.

I hope the info here will shed a little more light for me. I really think I am IR and suspect it could have been a factor in my relapse.

[Cory255]

Very interesting how my HOMA1 score is 2.04 and my HOMA2's 1.2.

That sounds a lot better with the HOMA2 score.  Thanks.    

[nygirl7]

I think this is the most I ever understood IR.

http://www.huffingtonpost.com/susan-b-dopart-ms-rd/weight-loss-tips-are-your_b_598250.html?ir=Daily%20Brief

[willing]

the discrepancy between Homa1 and Homa2 is an interesting aspect of the IR world. I'll post what some reading on the subject dug up when I have  a bit more time but here's what seems to be the gist of it:

- Wallace and coworkers introduced HOMA1 in '85 as a measure of IR that was easier to obtain than the gold-standard assay (euglycemic clamp)

- in '96 they modified the index to apply a non-linear (and more accurate) fit to the underlying data - HOMA2.

- you can get a rough idea of the difference between the two indices from Fig. 2 of a (free access) summary of HOMA usage published in '04
http://care.diabetesjournals.org/content/27/6/1487.full

- as the authors note, there's a much less accurate fit to the data with HOMA1 and the index tends to  underestimate your insulin sensitivity (%S) "the equations were based on the 1985 HOMA1 model, which was calibrated to an insulin assay used in the 1970s, and systematically underestimate %S and consequently overestimate %B when compared with newer assays" (that is,  HOMA1 makes you look more IR than you are)

- nevertheless, essentially *all* the studies that have found correlation between high HOMA and bad things (failure to SVR, increased fibrosis, increased HCC risk)  have used the HOMA1 index. The reason, as best I can make out, is that Matthews et al never got around to publishing the non-linear fit equations which remain buried in the calculator they implemented and make available for download. This doesn't mean the correlation is invalid, just inaccurate.

Overall, the high HOMA/bad-things correlation seems valid (lots of support) but based on  studies that used a HOMA measure *known* to be inaccurate. Bottom line is that if  you suspect IR is an issue calculate your %S with the updated HOMA2 index and/or check with your Dr. about a euglycemic pump test before deciding it's a problem -it may not be.

[Cory255]

You stated--, "Ranges for HOMA1, HOMA2, scores generally seem to consider lt 2 OK."

HOMA1 & HOMA2 are two completely different calculations.  Any score GREATER than 2 means your IR (with HOMA1).  My HOMA1 score is 2.04.  I'm IR!  

As of right now it is unknown when IR starts with the HOMA2, (2 definitely wouldn't be OK),  IR probably starts somewhere in the range of 1 maybe 1.1.  

[willing]

the free-access paper linked above
http://www.ncbi.nlm.nih.gov/pubmed/10868826
measured median HOMA1 of 2.7 among "490 healthy nondiabetic volunteers".

Also HOMA1 and HOMA2 were developed by the same research group at Oxford with HOMA2 being  an improvement/refinement  over HOMA1. As noted in the quote above (that paper is also free access)  the group that developed the test is well-aware that HOMA1 systematically underestimates insulin sensitivity, a problem they believe is fixed in HOMA2. Your HOMA2 score is very close to 1. Insulin resistance may be a problem for you, but it doesn't look that way from the numbers. Confirming with a Dr. that it's a problem before assuming there's something to fix may be a good idea.

[Cory255]

Most studies systematically use HOMA1 for data.

Mean being the average, median being the middle number in a set, & mode being the # that occurs most often.  

It was confirmed that I'm IR.  I'm just slightly into that range.  Should be able to sort it out a lot easier that way.  

[Cory255]

HOMA1-IR = (FPI (mU/L) x FPG (mmol/L))/22.5

HOMA1-%B = (20 x FPI (mU/L))/(FPG (mmol/L) – 3.5)

Where FPI is fasting plasma insulin and FBG is fasting plasma glucose; to convert mg/dL to mmol/L, simply divide by 18.

The original model did not account for differences between hepatic and peripheral insulin sensitivity, increases in insulin secretion or decreases in hepatic glucose production for plasma glucose concentrations above 180 mg/dL, renal glucose losses, or the contribution of circulating proinsulin.  An updated HOMA model (HOMA2) has since been created, however it is a computer model and has no simple equation but it adjusted to account for these variations.  It models insulin sensitivity (HOMA2-%S) where 100% is normal which is the reciprocal of insulin resistance (100/S%).  In addition, the original HOMA model uses equations that were calibrated to insulin assays used in the 1970’s which result in underestimation of %-S and overestimation of %-B.  With knowledge of these differences, it is therefore important when evaluating studies to determine whether the HOMA formula or the computer-based HOMA was used to quantify insulin resistance and beta-cell function.

[willing]

did a Dr. diagnose IR? that seems surprising with the numbers you posted. Unlike say fibrosis there are reliable gold-standard tests for IR that measure changes in  actual insulin/glucose dose/response levels instead of approximating them as HOMA does, so that seems the way to go if you want a definite answer.

Re homa1 vs homa2 yes agreed that essentially all studies have applied homa1 regardless of the fact the index systematically gives artificially high IR scores. To keep from comparing apples with oranges it seems best to use  HOMA1 for comparison with published studies and HOMA2 for a more reliable, corrected,  'absolute' indication of whether IR is an issue. For example, in one of the main IR vs SVR studies:
"Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients."
http://www.ncbi.nlm.nih.gov/pubmed/15765399
the average HOMA1   was 2.36 among SVRs and 3.76 among non-SVRs.

They also found better SVR rates among those with lower-than-average HOMA1, so there seems to be some motivation for pushing down your HOMA1 regardless of whether you're IR - though given HCV's known  effect on glucose metabolism the low HOMA1 group could also have had something else going for them - eg low VL.

(also sorry about my mistake in post above,  not sure why I wrote median HOMA1  of  2.7 among healthy volunteers,  that should be average).

[frijole]

Good thread

I read this with interest and have pulled prior blood work to see what it tells me.  My glucose is easy -- it is written as Glucose, Serum or GLU.  It is written in mg/dL so requires modification, per Willing.    I am having a problem finding any insulin resistance tests. I have a book -- "Mosby's Manual of Diagnostic and Laboratory Tests " which give what I thought were all the blood tests.  Under Insulin we have assay, autoantibody (IAA), blood glucose, C-peptide, and some growth factor tests.  So what, pray tell is an insulin resistance test,  and is it only run when there are high level glucose tests?  

I am always searching for reasons I relapsed.  Glucose is in range -- about 88 last time --  but  I would like to calculate this insulin resistance, .  If there is another test to ask for, I would like to ask my doctor for it.

frijole

[willing]

not much to it : (1) in addition to the glucose you also need an insulin or c-peptide measurement. For purposes of IR checking the authors recommend insulin which should be in the range 2-17 uU/mL (micro-units per milliliter) (2) make sure both are fasting tests as the levels can vary significantly around meals (3) after converting glucose from mg/dL just multiply the two together and divide by 22.5 to get your HOMA1 index. For HOMA2 you have to download the calculator from oxford
http://www.dtu.ox.ac.uk/homacalculator/index.php
either as an executable or an an excel control.

If it's an issue it seems more likely to show up as non-response than relapse but definitely a good thing to rule out. Glucose 88 looks pretty good. Mine tends to be at the high end of normal and broke past 100 last year triggering a slow down in my fig-bar rate which caused it to coast back to 92 - but insulin is way low.

[Trinity4]

It just makes good sense for non responders or relapers to check for IR prior to retreatment so there is time to do something about it.  Can't leave anything to chance after treatment has failed the first time.

Trinity

[nygirl7]

It certainly makes sense to me - anything that can help to cut down the potential for failure is a good thing, especially for a relapser because there had to be some reason that it didn't work in the first place really.
Every avenue should be pursued, agree 100% Trin!

[Bill1954]

Just a quick note to wish everyone good luck; it looks like old timer week in here with Frijole ( I just now noticed she fixed the spelling of her nom de plume:o)) and Willing gearing up for another run at this.

I sure wouldn’t discourage folks to inquire about their insulin resistance; it seems there’s been enough talk in scholarly studies recently to warrant investigation where indicated. I do want to point out, however, that I was *very* insulin resistant throughout my last treatment, but went on to SVRland anyway. Sooo, it seems that IR doesn’t preclude successful HCV therapy outcome, although it certainly might hinder it.

At one point, towards the end of that last treatment, I was maxed out on oral antidiabetic meds, and still required up to 115 units Lantus insulin just to keep fingerstick testing <200 mg/dL. Hehehe, I had 50 unit syringes, so it took three injections per sitting to get it all in :o). Those days were something else…

I’m managing blood glucose much better now; sure diet and exercise make a difference, and are large players in DM management. I’ve reduced my oral meds, and haven’t required *any* insulin since December ’08. I wonder how much of this is attributable to improved liver function, etc. Hepatic release of glucose is an important factor, I’d assume, and might have improved as a result of SVR…

Anyway, good luck to everyone,

--Bill

[willing]

thanks Bill, good comments. The good old days huh? and why couldn't they get you some larger unit syringes? Anyway, good all that is behind you and balance is looking better. The virus' mucking with glucose metabolism seems another excellent reason to get rid of it.

My vote for the single most crucial factor to check out for those wondering about IFN response is one's IL28B variant, but HOMA-IR score, BMI and  vitD level are all definitely  worth checking.

[Cory255]

IR seems to be the new PREDICTOR of SVR.  Insulin Resistance impairs sustained response rates to Peginterferon & Ribavirin for people with Hep C.

It is also noted:  Most Dr's are not aware the roll IR plays or how to compute HOMA.

I found this website on my own... It seems to confirm a lot of what has been said...  

http://www.hcvets.com/data/hcv_liver/InsulinResist.htm

[Cory255]

HCV slowly damages the mitochondria through a process of oxidative stress.  Aerobic exercise helps produce more mitochondria and a high-protein diet boosts the benefit of exercise, which decreases insulin resistance.  

Being insulin resistant will impair you ability to achieve a sustained response to Chemotherapy drugs peginterferon and ribavirin...

Adding Metformin before and during Hep C treatment increases your odds of clearing...

http://www.hcvets.com/data/hcv_liver/InsulinResist.htm