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Impact of Obesity on Hep C and treatment of HCV

Impact of Obesity on Hepatitis C and Treatment of HCV

By Liz Highleyman

It is increasingly clear that obesity and associated metabolic abnormalities play a role in the progression of liver disease and poor response to hepatitis C treatment.

Obesity and the metabolic syndrome -- a cluster of conditions including insulin resistance and elevated blood fat levels -- is associated with steatosis (fatty liver), which in turn is linked with more severe liver fibrosis and a greater risk of cirrhosis and hepatocellular carcinoma.

As reported in the May 2006 issue of Gastroenterology, for example, a meta-analysis of data from more than 3,000 patients at 10 clinics in Italy, Switzerland, France, Australia, and the United States found that steatosis was "significantly and independently" associated with fibrosis in people with chronic HCV infection, and that addressing metabolic factors "appears important in the management of chronic hepatitis C."

Similarly, a study presented at the Digestive Disease Week 2006 conference in May confirmed the link between steatosis and liver disease progression. In a retrospective review of medical records from 223 chronic hepatitis C patients, researchers observed a significant relationship between steatosis and fibrosis, leading them to suggest that, "Efforts to control steatosis may therefore have an important role in halting HCV liver disease progression, particularly in persons who are non-responders to antiviral therapy."

How Do Obesity and Metabolic Factors Promote Liver Damage?

The mechanisms by which obesity and metabolic abnormalities promote steatosis and fibrosis are not well understood, but inflammation, autoimmunity, and altered levels of cytokines and hormones such as leptin and adiponectin may play a role.

A study reported in the April 2006 Journal of Hepatology showed that alanine aminotransferase (ALT) levels -- and whether ALT decreased with successful treatment with pegylated interferon/ribavirin -- were associated with markers of the metabolic syndrome, including high body mass index and elevated blood pressure, blood glucose, and blood fat levels. The authors concluded that ALT elevation (a marker for liver inflammation) "partially depends on the degree of derangement of fat and carbohydrate metabolism."

In the June 2006 issue of Hepatology, researchers from the Mayo Clinic reviewed mechanisms that may explain the link between obesity and liver disease progression.

Fat tissue secretes hormones called adipokines (including leptin and adiponectin) that regulate metabolism of glucose and lipids in the liver, and also modulate immune activity. Some adipokines promote the release of pro-inflammatory cytokines. Leptin appears to activate signaling pathways in hepatic stellate cells that contribute to inflammation and fibrogenesis. Obesity can cause insulin resistance, which promotes the accumulation of fat in liver cells; HCV, too, appears to directly induce insulin resistance, so obese patients with hepatitis C may have an additive effect. Oxidative stress related to inflammation, as well as elevated insulin levels, may interfere with interferon-signaling pathways. Finally, excess fat tissue reduces the amount of circulating interferon in the body during treatment, possibly due to impaired absorption after injection.

Different HCV genotypes seem to be associated with steatosis through differing mechanisms. Genotype 3 HCV appears to directly promote the build-up of fat in liver cells, while steatosis in genotype 1 patients appears to be linked with co-existing metabolic conditions such as insulin resistance.

Management of Obesity

The Mayo Clinic researchers reported that reducing body weight and improving underlying metabolic factors may help "overcome the low sustained viral response rates observed in obese patients infected with HCV."

The first-line approach to managing obesity involves lifestyle modification, including exercise and a healthy, balanced diet. Weight loss has been shown to improve insulin sensitivity, lower ALT levels, and improve liver histology.

If such measures are not adequate, anti-diabetes drugs such as metformin (Glucophage), pioglitazone (Actos), and rosiglitazone (Avandia) may also be used to increase insulin sensitivity, which may help reduce fat accumulation in the liver. While these medications have not yet been studied extensively in people with hepatitis C, there is data suggesting that they are associated with reduced ALT and improved liver histology in HCV negative patients with non-alcoholic fatty liver disease.

The authors also suggested that use of higher doses of pegylated interferon and ribavirin for extended periods might help overcome the lower response rates observed in obese patients. Weight-based dosing and longer treatment durations are currently the subject of considerable research, but the authors also suggested higher dosing based on levels of insulin resistance or amount of visceral fat, rather than body weight alone.

Together, these studies suggest that liver disease progression should be considered among the deleterious outcomes of obesity and the metabolic syndrome, along with diabetes and cardiovascular disease.

7/28/06

References

G Leandro, A Mangia, J Hui, and others. Relationship Between Steatosis, Inflammation, and Fibrosis in Chronic Hepatitis C: A Meta-Analysis of Individual Patient Data. Gastroenterology 130(6): 1636-1642. May 2006.

K Corey, A K Bhan, R T Chung. Steatos is Associated with More Severe Fibrosis in Chronic Hepatitis C. Abstract S1056. Digestive Disease Week. May 20-25, 2006. Los Angeles, CA.

D Prati, M L Shiffman, M Diago, and others. Viral and Metabolic Factors Influencing Alanine Aminotransferase Activity in Patients with Chronic Hepatitis C. Journal of Hepatology 44(4): 679-685. April 2006.

M R Charlton, P J Pockros, S A Harrison. Impact of Obesity on Treatment of Chronic Hepatitis C. Hepatology 43(6): 1177-1186. June 2006.
21 Responses
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568322 tn?1370165440
I think the responsability should be shared.  Doctors should know not to put people on medications that increase weight and blood sugar like the anti-depressant Mirtazapine.

Look at the first study that was done with 5 non-responders to see if using an insulin sensitizer (Actos) to decrease insulin resistance would increase SVR.   The two patients who had a poor response and their insulin resistance increased were both on psych meds that can cause high blood sugar (Olanzapine and Zopiclone).  As if that wasn't enough, when taken together, Actos causes the levels of Zopiclone to go up.

They're doctors.  They should have known those drugs can increase insulin resistance!  

I find it hilarious how they talk about their screw up and then switch responsability back to the patient (who BTW was NOT obese) ......


From a Letter to the Editor by F. Negro (one of the docs that participated in the study). Journal of Hepatology 50 (2009) 1267–1272


"Correction of insulin resistance in chronic hepatitis C patients not responding to the standard of care:
More questions than answers"


"In the INSPIRED-HCV trial, only one patient was infected with genotype 3a. This patient had extensive fibrosis and a mild steatosis affecting 20% of hepatocytes, but no overweight or arterial hypertension. Quite oddly, upon retreatment, her HOMA-IR score underwent a surge from 2.65 to 11, while serum HCV RNA level remained unmodified. We fear that this paradoxical increase may have been the consequence of a pharmacological interaction between interferon-alpha and two additional drugs, i.e. duloxetine (olanzapine) and zopiclone, which have been occasionally associated with glucose metabolism derangements.

We remain convinced that correcting insulin resistance is a rational option in chronic hepatitis C patients failing to respond to combination therapy. However, the modalities of this correction have to be fully explored.

The sequential administration of higher doses of insulin sensitizers seems a reasonable approach, but the  likely genotype specificity of the mechanisms underlying the insulin resistant state and the risk of pharmacological interactions should both be taken in consideration before designing clinical trials. Finally, one should not forget that the most effective way of correcting glucose metabolism disturbances consists in lifestyle interventions, such as diet modifications and increased physical activity, and that there is no excuse why chronic hepatitis C patients should be spared such interventions."
---------


I guess "hilarious" was not the right word....disgusted was more like it.

Co
Helpful - 0
Avatar universal
"I am certain that the alcohol reference was to "moderate alcohol consumption" which has been shown to confer significant cardiac benefits as well as some positive influence on blood sugar. Of course, any discussion of even moderate alcohol discussion should be restricted to those cases of no or mild/moderate liver damage. In that population I think it could be successfully argued that obesity presents a much greater risk to health than does moderate drinking (1 drink per day for females and 2 for men - generally speaking). I have several articles which support the benefits of moderate drinking but I have never seen one article on the benefit(s) of obesity so, in that context, I agree that obesity presents a greater risk - excluding alcoholics, of course. "

That's reasonable.  I can accept that premise.

What I'd like to see defined is what is meant by obesity.  I wouldn't want to go on BMI alone as that's imprecise.  Any indication on what's meant by that?  I recall a time when I was considered obese on pure BMI alone - being 5' 4" - but also being in pretty good physical shape as well - as I keep alluding to, no IR, no diabetes, low blood pressure, etc.  

""...This case also queried whether treatment should be withheld or delayed in a person with ongoing alcohol use. This patient reported moderate alcohol use (2 beers/day), a characteristic that should not be ignored. However, although perceived substance dependence is the major reason HCV patients are denied therapy,[2] available data do not support their exclusion. Studies have indicated that similar SVR rates are achieved among patients completing therapy who use alcohol vs those who do not use alcohol.[3,4] Because of higher discontinuation rates among patients using alcohol while receiving therapy, a more appropriate strategy in these patients may be to address their alcohol use concurrently with beginning treatment. The AASLD HCV guidelines recommend that HCV-infected patients be encouraged to abstain from alcohol consumption but also indicate that treatment is not contraindicated in this population...."

Interesting.  Brings up alot of questions.  From what I've read and recall, alcohol reduces the effectiveness of interferon.  Someone would really need those two beers a day or not really believe it's causing them harm to continue with such a thing on treatment, don't you think?  Now I've learned that fat distribution in the body can reduce the effectiveness of interferon.  I'm starting to wonder what else reduces the effectiveness of interferon and I'm wanting to see some stats now on how much it reduces effectiveness.  But .. back to your point....

I recall one person on here who was brave enough to state that he drank alcohol while on treatment - I believe it was one drink a day? - and felt he would not have gotten through treatment quite as effectively without it.  I would rather see someone having the odd drink here and there and getting through treatment than not at all if that's what it takes.  That's not a popular viewpoint but it's mine.  I would rather see no alcohol at all but .. when it comes down to getting through treatment or not, I think sometimes it's the lesser of two evils but only in the rarest of cases hopefully, not as a given.

To take it a step further and in keeping with the subject of the thread, I wouldn't want to deny treatment to an obese person either but rather look at each case individually and determine what that individual's risk factors were based on additional health issues that may or may not be present that are common due to obesity.  If someone is overweight but generally a good candidate for treatment due to the absence of those factors, then why not go through treatment if that's what they wish?  Do you see any problem with that?

Trish

Helpful - 0
179856 tn?1333547362
Because of higher discontinuation rates among patients using alcohol while receiving therapy"

So how do they really know how many SVRd or how well their livers made out in the long run?
Helpful - 0
Avatar universal
I am certain that the alcohol reference was to "moderate alcohol consumption" which has been shown to confer significant cardiac benefits as well as some positive influence on blood sugar. Of course, any discussion of even moderate alcohol discussion should be restricted to those cases of no or mild/moderate liver damage. In that population I think it could be successfully argued that obesity presents a much greater risk to health than does moderate drinking (1 drink per day for females and 2 for men - generally speaking). I have several articles which support the benefits of moderate drinking but I have never seen one article on the benefit(s) of obesity so, in that context, I agree that obesity presents a greater risk - excluding alcoholics, of course.

I found a recent case study from Clinical Care Options on treatment of a patient who drinks moderately. It's not exactly on point but it's quite interesting and contained information that I was not certain about. Here is an excerpt from the discussion.

"...This case also queried whether treatment should be withheld or delayed in a person with ongoing alcohol use. This patient reported moderate alcohol use (2 beers/day), a characteristic that should not be ignored. However, although perceived substance dependence is the major reason HCV patients are denied therapy,[2] available data do not support their exclusion. Studies have indicated that similar SVR rates are achieved among patients completing therapy who use alcohol vs those who do not use alcohol.[3,4] Because of higher discontinuation rates among patients using alcohol while receiving therapy, a more appropriate strategy in these patients may be to address their alcohol use concurrently with beginning treatment. The AASLD HCV guidelines recommend that HCV-infected patients be encouraged to abstain from alcohol consumption but also indicate that treatment is not contraindicated in this population...."
See:  http://tinyurl.com/yzkm4ya

Mike
Helpful - 0
Avatar universal
nygirl - how much weight exactly did Rocker lose?  I hadn't realized he was obese and had high BMI and that losing weight had been such a difficult challenge for him.

Mike - your quoted comments, while true in essence, don't go far enough.  The article itself is very compelling and goes more into the why's of this - back to obesity-related health issues that can impact disease progression and treatment outcomes.  I think that is very important to understand the why's which is why I started this thread.  GREAT article - it takes me awhile to digest and then extrapolate and this is all the time I have right now.  If a person understands the various factors related to obesity that can impact disease progression and those that impact treatment, then they can be much more intelligent about how to manage their HCV and their treatment.

No doubt about it - weight loss is an excellent strategy and I absolutely concur with this statement in your post

"These findings should shift the framework of doctor-patient discussions in the clinical setting and encourage a broad approach to patient management that goes beyond HCV therapy alone."   I hope people will read the article you're quoting to get the specifics on WHAT findings. :)  Later I'd like to pull out key parts of it.

On another note, this statement troubles me in another way:

"Current and future treatment regimens remain toxic, expensive, and suboptimal. As the nation debates who will pay for such treatment, the current paper underscores the “personal responsibility” option: Lifestyle modification affects outcomes in hepatitis C (and liver disease) just as it does for diabetes, heart disease, and lung disease."

That whole debate on how far we go in treating people for theoretically self-inflicted health issues - that "personal responsibility" nugget.  Aside from HCV, obesity .... if one applies "personal responsibility" to healthcare, the discussion can get both alarming and intriguing.

Thanks for posting this, Mike.  Superb article.  It's an area I don't think has been explored to this depth here and as your post states, awareness in this area is important.  Not sure I'd go as far as the authors in relegating alcohol below obesity just yet - I'd like to see the data on that.  Interesting food for thought, however.
Helpful - 0
179856 tn?1333547362
Hell its not easy but I am determined to get back to where I should be.  I am not however obese and can't imagine what that is like, it's got to be rough - the whole thing and I don't envy anyone the hard road.

I think people on here are just trying to get the info out so it's known. Look at rocker he did it - it takes a lot but with that and the PI it looks like he is SVR.  It is just important for people to realize that they should do everything they can BEFORE treatment in order to up their odds.  Too man people fail - it is better to get the facts out there for those who want to/can do something so they can have every single advantage possible.
Helpful - 0
Avatar universal
From Clinical Care Options:

Weight Loss: A Modifiable Lifestyle Parameter That Can Alter HCV Liver Disease Progression

"....This study indicates that weight is arguably the most meaningful modifiable lifestyle parameter that can affect disease progression. The clinical implications of the findings are enormous and self-evident: Clinicians are obliged to better counsel their patients with chronic HCV infection on the impact of weight. Perhaps instead of admonishing patients to never again sip an alcoholic beverage, the focus of the discussion should advocate weight reduction. These findings are particularly salient in the current era in which the HCV epidemic and the obesity epidemic are running a collision course.[7] Indeed, obesity likely acts as a 2-hit cofactor that worsens other liver diseases, not just hepatitis C.[8] No future research will allow the opportunity to duplicate the findings of this report; therefore, this study represents a landmark piece of work that can be extrapolated to all liver diseases and that should change clinical practice.

The current antiviral treatment landscape, although improving, remains bleak for HCV-infected patients with advanced disease. Current and future treatment regimens remain toxic, expensive, and suboptimal. As the nation debates who will pay for such treatment, the current paper underscores the “personal responsibility” option: Lifestyle modification affects outcomes in hepatitis C (and liver disease) just as it does for diabetes, heart disease, and lung disease.[9-12] Clinicians can now cite proof that weight loss improves HCV-associated liver disease whereas weight gain worsens it. These findings should shift the framework of doctor-patient discussions in the clinical setting and encourage a broad approach to patient management that goes beyond HCV therapy alone."

http://tinyurl.com/ylk69jw

Mike
Helpful - 0
338734 tn?1377160168
Great information and great thread, Trish. IT pertains to me personally since I relapsed and my HOMA score is 2.8.  

My doc is currently involved in conducting a study of this issue, esp as pertains to effects of HCV TX and the drugs mentioned in the article. The current data is not clear on whether or not there is a significant benefit to using these drugs prior to or during TX. I am going to watch this. Maybe my doc can provide me with more information.
Helpful - 0
Avatar universal
I just wanted to add - I've been told when I'm direct that it comes across harshly at times and if that's how my words are coming across to you, it's unintended.  I'm wanting to make a point.  I appreciate the dialogue on this with you.  It's all valuable.
Helpful - 0
Avatar universal
"It is a real shame that people would rather take meds then lose weight. This means taking meds the rest of their life once their bodies becomes dependent on the meds.

I know how hard it is to lose weight and I have to give it my best shot because I'm on the boarderline of the "syndrom".  I want to at least try and avoid taking the meds the rest of my life."

I don't think you DO know how hard it is to lose weight.  I can tell by your comments.  Do you really think people would "rather take meds then lose weight"?  I think down to a person, everyone would rather lose weight than be overweight.  If it was that easy, there wouldn't be a whole weightloss industry would there.  If you have some secret that everybody else has missed, you're missing a real opportunity to be fabulously wealthy because there are millions upon millions of people who would like to have it.  I really don't want to start a debate where there are comments from people who find it easy to lose weight and say things like "simple - eat less, move more".  My daughter would prefer to be thin.  We can't even discuss it.  I bring it up and she shuts me down.  Yes, losing weight would be the preferred number one way to go.  When you figure out how to make that happen for everyone, you should let us all know.

I don't think anyone would RATHER take meds.  The simple fact is that some people are overweight, cannot lose the weight at this point in time for whatever reason but still need to undergo treatment.  The one person posted in the other thread that she's horribly fatigued and achy all the time, hoping that treatment resolves that so that she CAN lose weight - she's Stage 3/4.  At least this information might allow her to address the factors that would make her treatment less successful.  
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545538 tn?1295992017
Thank you for giving more information and discussing what I think is an important topic. I feel badly that luckyliver2009 was so discouraged. Good luck!
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Avatar universal
My post simply saying lose weight and increase chances SVR.

I think my post is accurate.  Is it not true if you lose weight you do increase your chances of SVR?  Will losing weight before TX address the metabolic issues?

Most of the time losing weight is the only thing necessary to rid oneself of the metabolic syndrom. So many people could go off their Type 2 dibetes drugs, BP & Cholesterol meds if they just lost weight. I recall one study that said losing as little as 10lbs starts to decrease the metabolic syndrom #'s. And they continue to decline towards normal the closer you get to your recommended BMI.

It is a real shame that people would rather take meds then lose weight. This means taking meds the rest of their life once their bodies becomes dependent on the meds.

I know how hard it is to lose weight and I have to give it my best shot because I'm on the boarderline of the "syndrom".  I want to at least try and avoid taking the meds the rest of my life.
Helpful - 0
568322 tn?1370165440
Obesity is associated with insulin resistance....and insulin resistance causes a compensatory hyperinsulinemia.....and high insulin levels affect the response to Peginterferon in the first 24 hours.  It lowers RVR and SVR.

Since the response to interferon is affected within the first 24 hours, that means you have to get rid of the insulin resistance BEFORE starting treatment.

Co


J Viral Hepat. 2009 Oct 21.

Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance.

Bortoletto G, Scribano L, Realdon S, Marcolongo M, Mirandola S, Franceschini L, Bonisegna S, Noventa F, Plebani M, Martines D, Alberti A.

Summary. Insulin resistance (IR) reduces response to pegylated-interferon (PEG-IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment - insulin resistance (HOMA-IR) for assessment of IR in non-diabetic patients, and the 'acute' virological response to PEG-IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG-IFN/Ribavirin, serum insulin and HOMA-IR were assessed at baseline, while hepatitis C virus (HCV)-RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 +/- 8.51 U/L and mean HOMA-IR was 2.65 +/- 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus-RNA decay observed 24 h after the first injection of PEG-IFN was significantly lower (0.7 +/- 0.8 log) in patients with HOMA >/=3 compared with those with HOMA /=3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24-h response to PEG-IFN. Hyperinsulinaemia reduces the cellular response to Pegylated-interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti-viral treatment.

http://www.ncbi.nlm.nih.gov/pubmed/19878535?dopt=Abstract
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Avatar universal
It's one article so can't say it's alot of research however you're welcome :) - really, it was you opening up the topic.  I wish I'd understood these things earlier and hopefully it helps others who have doctors who don't talk about these things.
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Avatar universal
"very good info. i have read many studies that say the same thing, basically saying lose weight and increase your chances of becoming SVR. "

The reason I posted this is because this information goes deeper than your comment - "basically saying lose weight and increase your chances of becoming SVR" - it suggests that addressing the metabolic issues that may be present are important and not just the weight alone - and that addressing these can mitigate the weight factor to some degree.  It bears out Kathy's point, that the absence of those metabolic factors increases the odds for an overweight person going through treatment.  It also gives strategies for when it's not possible to get down to a "normal" weight before undergoing treatment and addresses the impact of different genotypes.  I think those various distinctions are important to understand when someone is trying to tailor their treatment to get the most bang for their buck so to speak to properly address and mitigate their own individual risk factors.  It also brings out how obesity can increase the progression of fibrosis and why, the why being something I was unaware of.
Helpful - 0
768754 tn?1373918737
Thank you for posting such good information!  Much appreciated.  
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Avatar universal
very good info. i have read many studies that say the same thing, basically saying lose weight and increase your chances of becoming SVR.
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Avatar universal
Deb, can we leave the sniping on the other thread and not carry it over?  Figured this is good information for discussion or simply to be aware of.
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545538 tn?1295992017
Thank you for all of your research and information.
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179856 tn?1333547362
The Mayo Clinic researchers reported that reducing body weight and improving underlying metabolic factors may help "overcome the low sustained viral response rates observed in obese patients infected with HCV."

Darn Mayo Clinic what do they know anyway sometimes.  I guess as much as the folks on this forum who don't care about people?


I love the last bullet point on here Do u have to be skinny to receive treatment? That is what Veggie Dip used to say remember and yet I almost didn't succeed and without 72 weeks wouldnt have for sure.

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223152 tn?1346978371
Good information
frijole
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