Entry point for hepatitis C infection identified

Entry point for hepatitis C infection identified
January 24, 2012

A molecule embedded in the membrane of human liver cells that aids in cholesterol absorption also allows the entry of hepatitis C virus, the first step in hepatitis C infection, according to research at the University of Illinois at Chicago College of Medicine.

The cholesterol receptor offers a promising new target for anti-viral therapy, for which an approved drug may already exist, say the researchers, whose findings were reported online in advance of publication in Nature Medicine.

An estimated 4.1 million Americans are infected with hepatitis C virus, or HCV, which attacks the liver and leads to inflammation, according to the National Institutes of Health. Most people have no symptoms initially and may not know they have the infection until liver damage shows up decades later during routine medical tests.

Previous studies showed that cholesterol was somehow involved in HCV infection. The UIC researchers suspected that a receptor called NPC1L1, known to help maintain cholesterol balance might also be transporting the virus into the cell.

The receptor is common in the gut of many species -- but is found on liver cells only in humans and chimpanzees, says Susan Uprichard, assistant professor in medicine and microbiology and immunology and principal investigator in the study. These primates, she said, are the only animals that can be infected by HCV.

Uprichard and her coworkers showed that knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells.

Bruno Sainz, Jr., UIC postdoctoral research associate in medicine and first author of the paper, said because the receptor is involved in cholesterol metabolism it was already well-studied. A drug that "specifically and uniquely targets NPC1L1" already exists and is approved for use to lower cholesterol levels, he said.

The FDA-approved drug ezetimibe (sold under the trade-name Zetia) is readily available and perfectly targeted to the receptor, Sainz said, so the researchers had an ideal method for testing NPC1L1's involvement in HCV infection.

They used the drug to block the receptor before, during and after inoculation with the virus, in cell culture and in a small-animal model, to evaluate the receptor's role in infection and the drug's potential as an anti-hepatitis agent.

The researchers showed that ezetimibe inhibited HCV infection in cell culture and in mice transplanted with human liver cells. And, unlike any currently available drugs, ezetimibe was able to inhibit infection by all six types of HCV.

The study, Uprichard said, opens up a number of possibilities for therapeutics.

Hepatitis C is the leading cause for liver transplantation in the U.S., but infected patients have problems after transplant because the virus attacks the new liver, Uprichard said.

While current drugs are highly toxic and often cannot be tolerated by transplant patients taking immunosuppressant drugs, ezetimibe is quite safe and has been used long-term without harm by people to control their cholesterol, Uprichard said. Because it prevents entry of the virus into cells, ezetimibe may help protect the new liver from infection.

For patients with chronic hepatitis C, ezetimibe may be able to be used in combination with current drugs.

"We forsee future HCV therapy as a drug-cocktail approach, like that used against AIDS," Uprichard said. "Based on cell culture and mouse model data, we expect ezetimibe, an entry inhibitor, may have tremendous synergy with current anti-HCV drugs resulting in an improvement in the effectiveness of treatment."

See:  http://medicalxpress.com/news/2012-01-entry-hepatitis-infection.html


Mike

[nygirl7]

Huh so maybe this is why we all start out with good cholesterol but after treating successfully it oftentimes goes sky high? The receptor involved is affected?

"ezetimibe was able to inhibit infection by all six types of HCV"

So wow this is sort of like the beginning of a vaccine in a way isn't it? THAT would be so so so huge...imagine people not getting HCV in the first place and never needing to even worry about IFN or anything again?  That's a nice dream!

[frijole]

Wow, Mike.  This is amazing and it is already available.  It sounds like the most perfect thing for people that have had a transplant but were not able to treat for or didn't cure the hepatitis C before transplant.

How are you doing?  Still spinning?
bean

[Aaron57]

MM - Thanks for the post & very interesting research !

[jules2551]

I have to agree with NYgirl as maybe a vaccine is in the making.  That would be fantastic!!!  So your cholesteral went sky high after successfully treating?  Mine is average for women right now...trying to lose a few pounds and get that number down also.  Interesting

[mikesimon]

Hepatology. 2009 Oct;50(4):1030-7.

Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up.


Gastrointestinal Unit, Massachusetts General Hospital

Abstract

Hepatitis C associated hypolipidemia has been demonstrated in studies from Europe and Africa. In two linked studies, we evaluated the relationship between hepatitis C infection and treatment with lipid levels in an American cohort and determined the frequency of clinically significant posttreatment hyperlipidemia. First, a case-control analysis of patients with and without hepatitis C was performed. The HCV Group consisted of 179 infected patients. The Uninfected Control Group consisted of 180 age-matched controls. Fasting cholesterol, low density lipoprotein (LDL), high density lipoprotein and triglycerides were compared. Next was a retrospective cohort study (Treated Hepatitis C Group) of 87 treated hepatitis C patients with lipid data before and after therapy was performed. In the case-control analysis, the HCV Group had significantly lower LDL and cholesterol than the Uninfected Control Group. In the retrospective cohort, patients in the Treated Hepatitis C Group who achieved viral clearance had increased LDL and cholesterol from baseline compared to patients without viral clearance. These results persisted when adjusted for age, sex, and genotype. 13% of patients with viral clearance had increased LDL and 33% experienced increases in cholesterol to levels warranting lipid lowering therapy. CONCLUSION: Hepatitis C is associated with decreased cholesterol and LDL levels. This hypolipidemia resolves with successful hepatitis C treatment but persists in nonresponders. A significant portion of successfully treated patients experience LDL and cholesterol rebound to levels associated with increased coronary disease risk. Lipids should be carefully monitored in persons receiving antiviral therapy.

See: http://tinyurl.com/7ty6sve

[jules2551]

Thanks Mike...each and every day I learn something new

Jules

[LookingForward12]

This is very interesting. I have incredibly high cholesterol and have often wondered how it might relate to my HepC. So, there might be some sort of relationship is very interesting.

[curiouslady1]

Thanks Mike.  I was wondering why my cholesterol level has shot up 40 mg. since I started treatment.

[Willy50]

Thank you Mike for 2 good articles

[mikesimon]

HCV infection is generally associated with lower cholesterol. Frequently, patients who achieve SVR experience higher cholesterol numbers.

curiouslady - if there is no active infection then that is a possible -perhaps likely - explanation. It's one on the negative side effects of SVR. My cholesterol was always in the nineties when I was infected. Now it runs in the 150 to 165 range. It's not high but it is a lot higher than I ever saw it before  I became SVR. Of course, I never looked at any numbers until I found out I was sick. I assume that my genetics predispose me to low cholesterol because it sure isn't my diet - that's for sure.

Mike

[orphanedhawk]

Thanks for sharing this intriguing information.

[curiouslady1]

Thanks again for the extra commentary.  It is the only number that has gone up.  On my trial the PI told me not to change a thing.  Makes sense as how can one do comparisons otherwise?  So my eating habits, exercise etc. stayed stable.  As this is an open label trial I have all my numbers.  The cholesterol count was done at Day-1 and week 4, 12, 16.  I went UND at about week 1.5.  By week 4 cholesterol had gone up 34 mg.  Prior to that, as near as I can tell, it had fluctuated about 10 mg.   I hope it doesn't get worse.  

I guess this is the down side of doing a trial.  They often don't tell you to lose weight before you start or advise you to change things in mid trial.  However, their criteria for recruits for this trial is 35 BMI at entry (BMS 790052 + PSI 7977).  I don't know if this is the reason for the BMI limitation for this particular trial but those who treat in the future whether with trial or without might take this eventuality into consideration so as to protect their heart. As they say "a word to the wise is sufficient".  

Note to anyone reading this post:  Those who want to do the BMS/PSI trial extension coming up might want to remember that the BMI < or = 35 criteria remains the same although it may not be listed in the clinicaltrials.gov page.  Gonnab actually heads uped me on this one and when I checked with my trial coordinator she confirmed.  

[nygirl7]

Mine was perfect before I treated then shot up to 250 or something after treatment. Even my good cholesterol which is always way above average (probably the only good thing about it me how high it was) went DOWN! My BP one day was 190 / 100 or something close to that, the doctor was freaking out. I tried to relate the hcv conversation but as a GP he had no need to hear it or imagine why I was saying it he was just like you need LIPITOR NOW.

then of course I was scared of taking it because the 'dont take if you have liver damage' commercials however it has dropped my cholesterol back to almost normal levels and my good cholesterol has zoomed up again.  I guess if you monitor your liver enzymes you are fine taking it and might just save yourself heart problems.  so dont be a chicken like me it's good stuff - just as Michael always told me.  He's more reliable than a doctor to me.  :)

(PS My parents both have extremely high cholesterol I know i am predisposed to it, it's just so sad that the one good thing about active infection is the low cholesterol level - dang who knew HCV would be good for anything ;)

[UKgirl55]

I don't quite understand this study. I'm not overweight (in fact I'd like to put on weight), but my cholesterol level has been on the high side. I haven't treated yet. Am I wrong in thinking the body naturally raises the cholesterol level to help stop the virus from entering the cell? If your cholesterol level has gone up during tx...maybe this is actually good?? Of course, once you're off tx and cleared of the virus, you can then take medication to lower the cholesterol if need be.

Am I totally not understanding what's being said?

[curiouslady1]

Hey UK,  I don't understand the mechanism.  Maybe Mike will respond if he does.  But I do understand the implications.   I wonder if people planning to treat, like yourself, might want to evaluate with their doc whether they need to be on a cholesterol lowering med before they start? If considering a trial, they will often not want you to change anything midstream.   On the other hand, what is "high" for you?  I was bordering at the limit before I started treatment and occasionally going over the limit.  But not like this.  I have to do what NYgirl did and really attend to this issue for myself personally.

[curiouslady1]

Mike, this seems to me to be a really important post.  I dont want to be alarmist or anything but it is critical for some people to know this info.  Perhaps it would be helpful to bump it up after a week or two or investigate further the implications for other members.  My reasoning is this:  Many if not most of us who are treating and will be treating in the future are middle agers or late middle agers all the way up to seniors.  Often the cut off for treating is 70 but that leaves a lot of leeway.  And many are fighting the onset of aging effects.  Just because we cure HepC doesn't mean we are home free.

I just think it would be a great service if you posted this information periodically, even under a different title, so others who may need to know will take notice and so it seeps its way into the lore of this forum.  I have added it to my journals but people don't read that often.  I plan to prowl other forums and heads up people there too.  

[1oftheclub222]

This is interesting, my cholesterol has always been really good until just very recently, actually it was a bit high for the first time when I found out I had the hep c...I'm suppose to go back for a follow up, I was going to watch what I eat, yadda yadda yadda....but now with the treatment maybe it will be worse?  

Hep C possibly helps control cholesterol...very weird...the disease has a softer side...

[mikesimon]

I don't believe the mechanism is completely understood. The following excerpt mentions 2 possible explanations for elevated cholesterol post SVR.
1) Improvement on fibrosis
2) Effect of HCV eradication on cholesterol mechanism

I suspect that it may be a combination of the two but that's just a hunch.

From:  Gut Liver. 2011 September; 5(3): 356–362.

The Effect of Antiviral Therapy on Serum Cholesterol Levels in Chronic Hepatitis C

See: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166678/



DISCUSSION
In the present study, serum TC level significantly increased at 24 weeks after EOT among those in SVR group after antiviral therapy for CHC, but not in non-SVR group. Pretreatment and post-treatment TC levels were both independently associated with grade of hepatic fibrosis, while achievement of SVR was marginally associated with post-treatment TC levels. These results suggest that the change of serum TC levels according to antiviral therapy may be caused by improvement of hepatic fibrosis secondary to viral eradication rather than by the elimination of direct effects of HCV to the cholesterol metabolism in infected hepatocytes.
Serum TC level represents total amount of endogeneously synthesized and exogeneously absorbed cholesterols, which are transported into blood by binding to lipoproteins including very low density lipoprotein (VLDL), low density lipoprotein (LDL), and apolipoproteins. Endogenous cholesterol is synthesized in hepatocytes via the mevalonate pathway.9,21 On the other hand, exogenous cholesterol is endocytosed as the form of cholesterylester of LDL in hepatocytes and hydrolyzed to free cholesterol and fatty acid.22 Because most of these metabolic processes of lipid occur in the liver, serum TC level is closely related to the severity of liver diseases.1,2

Meanwhile, HCV has been documented to be able to interrupt lipid metabolism directly. HCV binds to LDL receptors in the membrane of hepatocytes for entry into the cells,7 and HCV particles are released from hepatocytes via VLDL secretion pathway.7,9,23 Moreover, HCV requires geranylgeranyl-pyrophosphate (PP) in the mevalonate pathway for replication, which may result in hypocholesterolemia, because HCV-infected cells spend most of the mevalonate as a substrate for geranylgeranyl-PP, rather than synthesis of cholesterol.22,24 Besides inhibition of cholesterol synthesis, HCV could impede cholesterol secretion into blood via the VLDL secretion pathway.23,25 These findings suggest that HCV itself may play a role to induce hypocholesterolemia independent of hepatic fibrosis, however, it has not been confirmed in human.

Many investigators have reported that reversals of hypocholesterolemia after antiviral therapy for CHC were observed among patient infected with HCV genotype 3, but there have been limited studies on the change of total cholesterol levels during and after antiviral therapy in genotype 1 and 2 infections.11,13,14,26 For the changing pattern of TC levels during antiviral therapy for genotype non-3 CHC, some studies have shown gradual increase of TC levels,11,13 while other studies14,27 have shown decrease of TC levels which was compatible with our results. The present study clearly showed that SVR resulted in reversal of hypocholesterolemia in patient infected mostly with genotype non-3 (98.9%).
On the other hands, the mechanism of reversal of hypocholesterolemia in HCV genotype non-3 infection can be different from that in genotype 3 infection. Thus, we hypothesized that the serum TC levels may increase after successful antiviral therapy by either eradication of HCV (SVR) or improvement of hepatic fibrosis which follows after viral eradication. To search the underlying reason for the increase of TC levels after SVR, we searched clinical variables associated with serum TC level, at pretreatment and post-treatment. Consequently, pretreatment TC level was inversely correlated with severity of liver fibrosis indicated as platelet count, METAVIR grade, Child-Pugh score and APRI. Although pretreatment TC level did not predict SVR in patients with genotype 1 or 2 infection, the elimination of hepatitis viruses from the liver was associated with the improvement of fibrosis grade and APRI. Those findings have not yet been sufficiently reported.

In addition, APRI scores decreased significantly in the SVR group than those in non-SVR group during and after antiviral therapy. As APRI is a simple and valid serum fibrosis marker,20,28 rapid reduction of APRI score may reflect a remarkably dynamic process related to improvement of liver fibrosis and inflammation during antiviral therapy. According to the multivariable analysis, APRI was the independent variable associated with the change of serum TC level after antiviral therapy. On the other hands, the viral eradication as indicated as SVR showed a marginal association with the change of TC levels. Therefore, the reversal of hypocholesterolemia in genotype 1 and 2 infected CHC after successful antiviral therapy may be mainly caused by improvement of hepatic fibrosis secondary to eradication of viruses rather than by direct effect of HCV eradication on cholesterol mechanism in CHC. However, further large prospective study is warranted to distinguish which factor plays the dominant role in increase of serum TC level after achieving SVR.
Among many other factors affecting serum cholesterol levels, such as race, age, gender, diabetes, and body mass index (BMI),29 BMI is one of the important determinants.30,31 Therefore, decreasing pattern of TC level during the antiviral therapy in our results is probably related to the decreased dietary intake and loss of body weight due to anorexia and other adverse effects of the therapy. However, age and BMI which were expected to affect serum TC levels significantly showed p-value less than 0.1 as the correlation analysis, probably due to small sample size.

The limitations of this study included retrospective design, relatively small sample size, and single center experience. The subgroup profiles of serum TC, which include LDL, VLDL, and high density lipoprotein, along with fasting glucose level were not available in the most of our subject patients due to retrospective design. We could not extensively investigate factors related to exogenous cholesterol uptake, such as dietary intake or body weight change during the course of antiviral therapy.

In conclusion, serum TC levels increased in the SVR group after antiviral therapy for CHC. The change may be explained by the improvement of liver fibrosis rather than by the eradication of HCV per se. Further investigation is needed to elucidate molecular mechanisms for the reversal of hypocholesterolemia in sustained viral responders, especially under the consideration of the change of hepatic fibrosis.

[mikesimon]

Cholesterol and chronic hepatitis C virus infection

Hepatol Res. 2011 Jun 17. doi: 10.1111/j.1872-034X.2011.00838.x. [Epub ahead of print]

Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.

Abstract

Cholesterol is an essential molecule for the life cycle of the hepatitis C virus (HCV). This review focuses on the roles of cholesterol in HCV infection and introduces HCV events related to cholesterol metabolism and applications for cholesterol metabolism as a therapeutic target. HCV appears to alter host lipid metabolism into its preferable state, which is clinically recognized as steatosis and hypocholesterolemia. While hepatic fatty acid and triglyceride syntheses are upregulated in chronic hepatitis C patients, no direct evidence of increased hepatic de novo cholesterol biosynthesis has been obtained. Impaired VLDL (very low density lipoprotein) secretion from hepatocytes is suggested to increase intracellular cholesterol concentrations, which may lead to hypocholesterolemia. Clinically, lower serum cholesterol levels are associated with lower rates of sustained virological responses (SVR) to pegylated-interferon plus ribavirin therapy, but the reason remains unclear. Clinical trials targeting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, are being conducted using statins. Anti-HCV actions by statins appear to be caused by the inhibition of geranylgeranyl pyrophosphate synthesis rather than their cholesterol lowering effects. Other compounds that block various steps of cholesterol metabolic pathways have also been studied to develop new strategies for the complete eradication of this virus.

http://hepatitiscresearchandnewsupdates.blogspot.com/2011/06/cholesterol-and-chronic-hepatitis-c.html

[Idyllic]

The first thing I thought of was this seems vaccine oriented but the links I am missing as a layman to see the viability of that idea is how the immune response aspect would work. In part that's because of an article I read a few days ago:
http://www.medicalnewstoday.com/articles/239982.php

[LookingForward12]

Oh my - if my cholesterol levels are so high now (above 240), what in the world will it be like when I achieve SVR (I did have 'if' but decided to go with a more positive 'when')?  
On the other hand, I wonder if my high cholesterol has helped to keep my liver relatively safe from the effects of the virus over the past 30 years or so. My viral load (compared to some) when I started treatment was <4.1 million and that has only increased to that much over the past two years. My liver biopsy showed 'little to no scarring' and  my MRI just indicated inflammation.

@idyllic - the link seems to be broken

[burned74]

Thanks for posting this, Mike.

Isn't the main point here that this already approved drug could be used to protect existing cells and therefore inhibit HCV replication, thereby aiding in SVR?

Maybe this will be added to future regimens?

The researchers showed that ezetimibe inhibited HCV infection in cell culture and in mice transplanted with human liver cells. And, unlike any currently available drugs, ezetimibe was able to inhibit infection by all six types of HCV.

[mikesimon]

Yes, that was the point of the original article I posted.
We just got side tracked into the mechanism(s) by which HCV infection lowers cholesterol.

Mike

[curiouslady1]

I don't know what it means but it is interesting about how the body can adapt and balance things in some cases.  I also estimate I have had the disease for 40 years and little or no fibrosis as far as we can tell (admittedly from a recent fibrosure rather than biopsy).  

Everyone has heard the saying "if it ain't broke, don't fix it".  While I don't think that anyone should take this to heart with regard to infection; still, those of us who have been carrying this infection for many decades probably ought to think of how the body has adapted.   It would behoove us to take particular note about the delicate balance of body processes and functions in planning our treatment and follow up care esp. as it impacts extra hepatic mechanisms.  

[mikesimon]

I'm sorry. I didn't see your post until now.
I cannot predict what your cholesterol will be once you achieve SVR. My experience and that of several people I know is that cholesterol is likely to increase once the virus is eradicated. I also should tell you that I don't know anyone who had that high of a cholesterol while infected with HCV. The people I know were always thrilled that of all their blood test results their cholesterol always looked good. And then they achieved SVR and it didn't look so good anymore. It used to surprise a lot of people - before this was widely known.

I have no idea whether your high cholesterol protected your liver. I know many people who had normal cholesterol while infected and some of those had minimal histological evidence of HCV. I always say that basically some people are just lucky although I know there are probably host characteristics that would explain it. I just don't know enough to know what they are.

Mike

[curiouslady1]

Is it really that widely known?  I didn't know it.  Like Looking, my cholesterol was high going in.  I might have tried a little harder to get it under control before I started if I had known.  Oh well, hindsight etc.  

Thanks again for this very rich thread Mike.  

[willbb]

Mike and  burned: I am not entirely sure of this,however I thought I read somewhere  that this drug had some problems as it pertained to liver injury and causal of some warnings and recalls and such.

Not positive of that and don"t have time to look further right now but will.

Possibly this is the reason it has not been investigated  moreso for HCV tx.?
Best..
Will

[imrosari1]

New vaccine for hepatitis C underway
A new vaccine for hepatitis C had been developed by a team of experts recently. The first clinical trial for testing the efficacy of the vaccine has yielded positive results, as reported by Oxford University professionals.
The vaccine was developed by a collaboration of scientists from the Oxford University, the University of Birmingham and an Italian biotech company. This team aimed to use a new avenue to instigate a distinct arm of the immune mechanism than the one used in initial studies. This injection is formulated to enable T cell responsiveness to the more consistent areas of the hepatitis C virus, instead of striking the outer coat of the virus which keeps varying persistently.
“The outside shell of the hepatitis C virus is very variable but the inside of the virus is much more stable. That’s where the engine of the virus is, where we may be able to successfully target many of the crucial pieces of machinery. But we need T cells and not antibodies to be able to react to the inner components of the virus,” explained Professor Paul Klenerman of the Nuffield Department of Clinical Medicine at Oxford University.
In this preliminary trial, about 41 healthy persons were exposed to the vaccine. As per the results, the vaccine seemingly triggered a greater T cell response for combating the disease and the effects stayed for a minimum of 1 year. The response was similar to the impact seen in people when the virus is eliminated after affliction.
Further studies to gauge if the vaccine could also work for people already infected with Hepatitis C are underway. Considering that T cell responses often become weak in people suffering from chronic hepatitis C infections, this vaccine may be used to enhance T cell responses and boost the immune mechanism in the process.
The findings are published in the journal, Science Translational Medicine.

[mikesimon]

There have been some reports of increased liver enzymes and elevated bilirubin and jaundice with ezetimibe. It's often combined with a statin and some of the studies are of a combination of 2 drugs so it's a little confusing as to which drug has the major hepatic influence.

I did see this article:

Liver Transpl. 2009 May;15(5):504-8.

Safety and effectiveness of ezetimibe in liver transplant recipients with hypercholesterolemia.


"Hypercholesterolemia is a common problem among transplant recipients. Despite package-insert warnings about the potential side effects of the use of statins in patients with chronic liver disease, they are often prescribed for liver transplant recipients. Unlike statins, ezetimibe acts through inhibition of enterohepatic recirculation of lipids. We report the effectiveness and safety of ezetimibe among liver transplant recipients because this has been evaluated previously only in kidney and heart transplant patients. A consecutive cohort of 25 liver graft recipients with serum low-density lipoprotein (LDL) levels > 100 mg/dL (2.5 mmol/L) after a mean (+/-standard deviation) of 55 +/- 21 months following liver transplantation received ezetimibe (10 mg orally every day) for at least 6 months. Serum lipid profiles, liver and renal function tests, and dosages and blood levels of the immunosuppression drugs at baseline, 3 months, and 6 months were prospectively collected. The overall mean age was 58 +/- 12 years, and 56% were males. Statin therapy and fibrates were already being used in 32% and 20% of recipients for elevated LDL and/or triglycerides, respectively. The immunosuppression regimen included cyclosporine in 48% of subjects, tacrolimus in 32%, sirolimus in 48%, and mycophenolate mofetil in 44%; only 12% were on oral prednisone with a maximum daily dose of 5 mg. After ezetimibe was started, an 18% reduction in LDL values was observed [at baseline, 147 +/- 35 mg/dL (3.8 +/- 0.9 mmol/L), and at 6 months, 120 +/- 31 mg/dL (3.1 +/- 0.8 mmol/L); P = 0.010]. After 6 months, an additional 32% achieved the target LDL level of <100 mg/dL. None of the remaining variables, including immunosuppression drug levels, varied significantly during ezetimibe therapy. None of the subjects required adjustments in their pharmacological dosages. One discontinued ezetimibe 3 months later because of cost, 2 subjects had minimal nausea, 1 subject had myalgias without a rise in creatine phosphokinase, and 1 subject had a transient elevation (3-5 times) in liver enzymes from baseline with increases in the total and indirect bilirubin levels. In conclusion, among liver transplant recipients, hypercholesterolemia can be effectively treated with ezetimibe with few side effects and no interaction with immunosuppressive regimens."

http://www.ncbi.nlm.nih.gov/pubmed/19399742

[willbb]

Thx. Mike:
Along the same lines I had read this  and I remember seeing at one time about the regulators here in Can. reporting on it.
Yes... a little confusing on what exactly caused what ,however  possibly because of the conflicting info.   it has been put aside as an adjunct to HCV therapy.
Will

Regulators in Australia and Canada have warned since 2005 about the drug's potential to cause hepatitis, pancreatitis and depression.

/27/07)- Partial results of studies that had been conducted by Merck and Schering-Plough, showed the possibility that Schering-Plough's cholesterol medication Zetia, when combined with statin drugs might cause damage to the liver, and that this risk had not been revealed by the companies. The discovery of the unpublished research adds more fuel to the controversy involved in the failure of Schering and Merck to make a timely disclosure of the results of the Enhance study that we discuss in the items below.

A Schering executive, Dr. Robert J. Spiegel, when queried about the unpublished studies confirmed their existence. Dr. Spiegel went on to explain that Merck and Schering did not consider the studies scientifically important enough to publish the findings.

Before Zetia was approved in 2002, one FDA reviewer said it should not be cleared for use with statins, because the combination had caused liver damage in animals. In the last two years, scattered case reports of severe liver damage in patients taking Zetia in combination with statins have appeared in medical journals.

The label for Zetia contains only mild warnings about the drug's potential for liver damage. Regulators in Australia and Canada have warned since 2005 about the drug's potential to cause hepatitis, pancreatitis and depression. Most of the studies for which Merck and Schering have published results for Zetia covering only 12 weeks, which is not enough time for liver problems to develop in most patients.

The unpublished studies were conducted from 2000 to 2003 according to FDA documents but were not listed on the industry Web sites where campaniles are supposed to register the results of all drug trials that were ongoing after October 2002. When the FDA approved Zetia in 2002 it relied on trials that covered only 3,900 patients and lasted no more than 12 weeks.

The data from those trials indicated that Zetia might be dangerous when it is combined with a statin.

http://www.therubins.com/resource/data.htm

[mikesimon]

That's essentially what I've read. It is so often combined with a statin that it's confusing whether one drug or the other or the combination of the two is responsible for the hepatic side effects.
I thought the use of ezetimibe in the liver transplant population - although a  small cohort - suggested that it may not pose a significant risk. Close monitoring of liver enzymes and function would likely be protocol with ezetimibe.

Mike

[babs824]

yikes this is alot to absorb without a medical degree. my cholesterol has always been high and one month on lipitor made liver enzymes worse. all this was before successful tx. ive kinda been avoiding docs since i finished tx! recent reports show a link to use of lipitor and such as causing a possible rise in incidence of type 2 diabetes. my sis has hi cholestorol and now prediabetic after using lipitor for a few years. she is not over weight either. her triglicerides (triglycerides) have been going steadily up since the lipitor. sooooo if u are a woman be sure to do homework before u suddenly start on statins, b

[rkt0211]

I started taking the statin drug Lipitor for my high cholesterol. Soon after taking the drug my liver went south for a vacation. That was when they tested me and found out that I have Hep C. They think I caught it from a patient, as I am a healthcare worker. Still a mystery. Any how thanks for the post. Is their anyone currently taking that particular drug? What are some side affects? And why not more people on it?

[evangelin]

It looks like curcumin inhibits entry too but green tea and curcumin both mess with the same metabolic pathway that protease inhibitors use so a person wouldn't want to use them until after TX.  It is my plan to use both afterward for my husband especially in that transition time when your own normal immune function needs to kick back in and take over.   I don't necessarily think the cholesterol lowering drug is good for an already ailing liver but green tea and curcumin has the potential to be helpful to the liver in other ways too. I appreciate finding this information.  
Ev

[evangelin]

This is an earlier study that came out about that showed curcumin to inhibit the virus and it looks as if the above information me explain why it does.  I haven't explored the green tea aspect yet. I caution one more time not to combine green tea or curcumin with the TX drugs.
Ev
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FEBS Lett. 2010 Feb 19;584(4):707-12. Epub 2009 Dec 17.
Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway.
Kim K, Kim KH, Kim HY, Cho HK, Sakamoto N, Cheong J.
SourceDepartment of Molecular Biology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea.

Abstract
A polyphenolic compound from the curry spice turmeric, curcumin, is known to show anti-viral activity against the influenza virus, adenovirus, coxsackievirus, and the human immunodeficiency virus. However, it remains to be determined whether curcumin can inhibit the replication of hepatitis C virus (HCV). In this study, we showed that curcumin decreases HCV gene expression via suppression of the Akt-SREBP-1 activation, not by NF-kappaB pathway. The combination of curcumin and IFNalpha exerted profound inhibitory effects on HCV replication. Collectively, our results indicate that curcumin can suppress HCV replication in vitro and may be potentially useful as novel anti-HCV reagents.

Copyright 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

[evangelin]

I will add one more thing for anyone interested and then I will go back to my quiet place.
Ev
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  Research
Curcumin inhibits cholesterol uptake in Caco-2 cells by down-regulation of NPC1L1 expression
Dan Feng, Lena Ohlsson and Rui-**** Duan*

* Corresponding author: Rui-**** Duan Rui-****.***@****

Author Affiliations
Gastroenterology and Nutrition Laboratory, Biomedical Center B11, Institution of Clinical Sciences, University of Lund, Lund, Sweden

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Lipids in Health and Disease 2010, 9:40 doi:10.1186/1476-511X-9-40



The electronic version of this article is the complete one and can be found online at: http://www.lipidworld.com/content/9/1/40


Received: 8 March 2010
Accepted: 19 April 2010
Published: 19 April 2010


© 2010 Feng et al; licensee BioMed Central Ltd.


This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background
Curcumin is a polyphenol and the one of the principle curcuminoids of the spice turmeric. Its antioxidant, anti-cancer and anti-inflammatory effects have been intensively studied. Previous in vivo studies showed that administration of curcumin also decreased cholesterol levels in the blood, and the effects were considered to be related to upregulation of LDL receptor. However, since plasma cholesterol levels are also influenced by the uptake of cholesterol in the gut, which is mediated by a specific transporter Niemann-Pick Cl-like 1 (NPC1L1) protein, the present study is to investigate whether curcumin affects cholesterol uptake in the intestinal Caco-2 cells.

Methods
Caco-2 cells were cultured to confluence. The micelles composed of bile salt, monoolein, and 14C-cholesterol were prepared. We first incubated the cells with the micelles in the presence and absence of ezetimibe, the specific inhibitor of NPC1L1, to see whether the uptake of the cholesterol in the cells was mediated by NPC1L1. We then pretreated the cells with curcumin at different concentrations for 24 h followed by examination of the changes of cholesterol uptake in these curcumin-treated cells. Finally we determined whether curcumin affects the expression of NPC1L1 by both Western blot analysis and qPCR quantification.

Results
We found that the uptake of radioactive cholesterol in Caco-2 cells was inhibited by ezetimibe in a dose-dependent manner. The results indicate that the uptake of cholesterol in this study was mediated by NPC1L1. We then pretreated the cells with 25-100 μM curcumin for 24 h and found that such a treatment dose-dependently inhibited cholesterol uptake with 40% inhibition obtained by 100 μM curcumin. In addition, we found that the curcumin-induced inhibition of cholesterol uptake was associated with significant decrease in the levels of NPC1L1 protein and NPC1L1 mRNA, as analyzed by Western blot and qPCR, respectively.

Conclusion
Curcumin inhibits cholesterol uptake through suppression of NPC1L1 expression in the intestinal cells.

Introduction
Elevated plasma cholesterol levels constitute a major risk factor for atherosclerosis and coronary heart diseases [1]. The levels of plasma cholesterol are influenced by de novo biosynthesis, absorption in the gut, and the removal of cholesterol from the blood [2]. The intestine plays a major role in regulating cholesterol homeostasis and about 36% reductions of plasma cholesterol could be achieved by total inhibition of cholesterol absorption [3]. Absorption of cholesterol is a multi-step process in which cholesterol is micellized by bile acids in the intestinal lumen, taken up by the enterocytes, assembled into lipoproteins, and transported to the lymph and the circulation. Niemann-Pick C1-like 1(NPC1L1) protein has been identified as a specific transporter for cholesterol uptake at the surface of plasma membrane [4]. Ezetimibe is a well-known inhibitor of NPC1L1 and has been widely used as an effective cholesterol-lowering drug for treating patients with hypercholesterolemia[5].

Curcumin is the major constituent of turmeric curcuminoids and has been found to have antioxidant, anti-tumor, anti-inflammatory properties [6-8]. Besides these well-known effects, curcumin was also found to affect lipid metabolism. More than 30 years ago, Rao et al showed that administration of curcumin decreased cholesterol levels in the blood and liver in normal animals [9]. Similar reductions were also identified thereafter in diabetic animals and animals fed high fat [10-12] and in healthy humans, varied with the dose, age and the period of administration [13-15]. The mechanism underlying the hypocholesterolemic effect may be related to the upregulation of LDL receptor [16,17]. Since plasma cholesterol levels are also influenced by absorption of cholesterol in the gut, we, in the present study, addressed a question whether curcumin affects the cholesterol uptake in the enterocytes.

[babs824]

this is good news for post tx folks like me who do not dare mess with statins. we have a great spice store. can i just buy organic tumeric? thanx ev, babs