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2010-10-06 Arun J. Sanyal MD Nonalcoholic Steatohepatitis, NASH and Vitamin E

An Interview with Arun J. Sanyal, M.D.

October 6, 2010, by Kirkham R. Hamilton, PA-C
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KIRK HAMILTON: Hi my name is Kirk Hamilton your host of Staying Healthy Today, and our message is simple: To provide you credible usable health information from our interviews and our educational resources to help you Stay and Be Well in the busy modern world. Please take a few moments before or after listening to this interview to browse through the Prescription2000.com website, the home of Staying Healthy Today Radio, for our free educational services.

Today's show topic is "Nonalcoholic Steatohepatitis or NASH and Vitamin E Therapy." Our guest today is Arun J. Sanyal, M.D., Dr. Sanyal has coauthored a paper entitled "Pioglitazone, Vitamin E or Placebo for Nonalcoholic Steatohepatitis," published in the May 2010 issue of the New England Journal of Medicine.

Welcome Dr. Sanyal. Thanks so much for coming on the show today.

DR. ARUN SANYAL: It's my pleasure.

KIRK HAMILTON: Can you tell me a little bit about your educational background and what your current position is and your responsibilities?

DR. ARUN SANYAL: Yes. I'm a gastroenterologist and a hepatologist by training and I am currently the Chair for the Division of Gastroenterology, Hepatology and Nutrition at Virginia Commonwealth University in Richmond, Virginia.

KIRK HAMILTON: Can you tell me - nonalcoholic steatohepatitis seems like a big long fancy name and the other term is NASH, and in some cases when I looked on some health websites it was fatty liver disease. Can you explain exactly what nonalcoholic steatohepatitis is?

DR. ARUN SANYAL: Well there are two parts to the name. First of all we do not believe this is related to consumption of alcohol in harmful amounts. Therefore it is nonalcoholic, and steatohepatitis is just a fancy way of saying that there is accumulation of fat in the liver and that fat is actually injuring and producing inflammation in the liver.

KIRK HAMILTON: So how does it come about? Is this a lifestyle disease or is this a medication induced disease, or what is it?

DR. ARUN SANYAL: It's a combination of things, clearly our genetic background is important, what we eat is important, our lifestyle is important. So it is very closely linked to our national problem with obesity. However, you do not have to be obese to get this disease and everybody who has this disease is not obese and everybody who is obese does not have this disease. So while it is closely linked to obesity, there are some distinct liver-specific aspects to it which are determined by our genetic background.

KIRK HAMILTON: So what type of public health issue is this? Is this infrequent or very frequent?

DR. ARUN SANYAL: We believe this is a major public health problem for several reasons. One, this is extremely common. Roughly 4 to 5 percent of the U.S. population has this condition. Number two, most people who have this condition have no symptom so they are unaware that they have anything wrong with their liver. And number three, many physicians, particularly primary care physicians, are unaware of the significance of mild elevations in routine blood tests that they might obtain which include liver enzymes and pass it off as a nonspecific thing, but that might be the only signal there's something wrong. So it is often missed even by healthcare providers until the disease becomes more advanced. And it is now being linked also as a risk factor for development of liver cancer. So for a variety of these reasons it is very prevalent, you may not know that you have it unless you get checked out, and it might set you up for cirrhosis and liver cancer. So if you put these three things together that's pretty serious. I wouldn't want anyone in my family to have it.

KIRK HAMILTON: So let's say I'm a primary care physician assistant and I'm screening someone on a yearly physical and maybe they don't look grossly overweight and they have subtle elevation of liver enzymes and they're not really complaining of anything. What do I do next to rule out this condition?

DR. ARUN SANYAL: This is a very common situation. What I would do is to follow the patient very closely. I would advise them about healthy living, which is eating a balanced diet, maintaining their body in a normal range and being physically active, avoiding alcohol consumption in harmful amounts, which is typically more than three to four drinks - typically more than three drinks in a day for men and two drinks a day for women. And recheck their numbers and if their numbers are persistently elevated for more than three or four months I would then send them to be evaluated further.

KIRK HAMILTON: So is the next test - what would be the next test if I referred to a gastroenterologist or is there some screening MRI or whatever, CAT scan, that I could do on the liver? How would you assess that?

DR. ARUN SANYAL: Most people would get an ultrasound which is sort of the cheapest test, you know, which would show an echogenic liver which means the liver looks very bright on an ultrasound. Unfortunately, it is not highly specific. It is sensitive, but it is not specific. But that at least tells you that you're sort of on the right track. And at that point you have to think about the likelihood that this is indeed NASH as opposed to just a fatty liver. I should back up over here for a second and tell you that if you look at the spectrum of liver disease related to fat accumulation, you can have just fat accumulating in the liver in which case it's called a fatty liver, or you could have fat producing injury to the liver in which case it is called NASH or steatohepatitis. And both of these together are called nonalcoholic fatty liver disease. So you need to know if this is NASH or if it's just fatty liver because if you have NASH, then that has significant health implications for the patient and you might do additional things for the patient. So unfortunately, the only way to know that is with a liver biopsy at this point in time. So you really have to try and cherry-pick who you want to take forward for a biopsy so you should look at risk factors that might tell you that the likelihood of having NASH, the more aggressive form of the disease, is high, and so particularly if somebody is very obese, if they are over the age of 50, if they are diabetic, if they have multiple features of what we call the metabolic syndrome such as high blood pressure, high cholesterol, etc, then it's much more likely that the liver disease is also more significant. And those might be the patients that one might consider for a biopsy to evaluate whether this is indeed NASH. At the same time,
if the platelet count looks slightly low, it is possible that NASH might already be quite advanced and then you would do the biopsy because you are worried that the disease may already have progressed towards cirrhosis.

KIRK HAMILTON: So a minimum that a primary care would refer to you, he should have screened for liver enzymes for several months if they're, you know, slightly elevated and possibly done an ultrasound before referral.

DR. ARUN SANYAL: Right, because most patients with NASH actually do not have very high liver enzyme elevations. In fact, if the liver enzymes are more than 250, 300, one should worry that there's something else going on. The majority of patients have liver enzymes which are 1 to 3-fold elevated above the upper limit of normal.

KIRK HAMILTON: Would you have recommended that like hep (hepatitis) C was screened for before then?

DR. ARUN SANYAL: Oh yes. When you come in with abnormal liver enzymes the first thing to do is obviously to make sure you exclude out all the usual suspects like hepatitis B and C, and look at an iron panel in the appropriate population and so on and so forth. And usually all of those are negative. What you're left with are people with elevated enzymes for which you don't have an obvious explanation. In that setting, about 75 to 80% of the time it is fatty liver disease and then what you have to figure out is whether that is NASH or whether that's just fatty liver. And the likelihood of it being NASH is increased if you are particularly obese, older, diabetic, and have multiple features of the metabolic syndrome.

KIRK HAMILTON: We're talking to Dr. Arun Sanyal, who is Professor of Medicine and Chairman in the Division of Gastroenterology at Virginia Commonwealth University Medical Center in Richmond, Virginia, and we were talking about nonalcoholic steatohepatitis or NASH and the area that caught my interest was vitamin E therapy, so I thought we could enter into that discussion. What was it with regards to the pathophysiology of NASH and the biochemistry of vitamin E that you wanted to put those two together to see if there could be any reduction in that condition?

DR. ARUN SANYAL: So about ten years ago we showed that humans who have NASH have what's called oxidative stress where they - in the liver. Now oxidative stress means you're producing a lot of what are called reactive oxygen species or reactive chemicals that bind to the structures within the liver cell and cause them to fail or not work properly. Particularly, one of the targets is what we call the mitochondria, which is essentially where we generate the energy for every cell. Vitamin E is a well known antioxidant and therefore we chose vitamin E to study as a treatment of NASH. We initially did a pilot study, now almost eight or nine years ago, and the results were promising. Simultaneously a study was done in children by another group and Dr. Levine showed that the liver enzymes in the blood tests improved on vitamin E and so armed with those two pieces of information, we decided we really needed to establish definitively whether it worked or it did not work. And that was the basis for doing the present trial, which was a trial undertaken by the NASH Clinic Research Network, which is a network of eight centers put together by the NIH specifically the NIDDK. This trial looked at people with severe NASH and were nondiabetic and looked at two different drugs. One was called pioglitazone and the other one was vitamin E, and they were both compared to no treatment at all with a placebo. And it turned out that vitamin E reversed the disease in about 40, 41 percent of patients who had severe NASH, compared to about 19% of people on placebo who improved "spontaneously." Now you have to remember that in a study people get followed very carefully. They are seen frequently by healthcare providers, they get counselling, so there is a background effect of just being part of a clinical trial which makes people healthier than they otherwise would have been.

KIRK HAMILTON: Could the difference between plain fatty liver and NASH, which is harmful, be the fact that that individual might have a low amount of dietary antioxidants or a poor nutrient diet that would make the difference?

DR. ARUN SANYAL: We have looked at that and it cannot be explained simply on the basis of diet alone so the answer is not as easy as eating more fresh fruits, etc., which have antioxidants. However, because you know the antioxidants that you eat in your diet, they have - it provides you a general level of antioxidants within the body. But the problem that comes up when these diseases cause oxidant stress is that at the location inside the cell where the oxygen stress is happening, you have to get the active compound to that location and that becomes a lot more tricky. Just because there's something circulating in the blood does not necessarily mean that in the interior of the cell deep inside our body where the action is at the level of the molecules that you can actually get the drug in enough amounts right to where it needs to be.

KIRK HAMILTON: So that's probably why you use more of a pharmaceutical dose of 800 IU per day of vitamin E correct?

DR. ARUN SANYAL: That was the rationale.

KIRK HAMILTON: So let me ask you this. Vitamin E has a lot of you know alpha, beta, gamma, they're different antioxidants -

DR. ARUN SANYAL: Absolutely, so this was the alpha form. It's the natural form. Some of the other forms may be more biologically active but it gets excreted faster as well and they're not really that suitable for long term human consumption, plus their toxicities have not been fully worked out. So we use what has been around for a long time. It is generally considered fairly safe and we know that at least in the short term it is very well tolerated. So we use the natural form which is alpha tocopherol and it is the RRR form of alpha tocopherol which is as I said it's the natural form.

KIRK HAMILTON: Was it in a single dose or divided dose and was it with meals -

DR. ARUN SANYAL: It was in two divided doses because every patient took two pills. But you know if you're taking a drug like this for long term, particularly a drug that is fat soluble and essentially partitions into all the lipid compartments in the body it probably does not make a difference whether you take it once a day or you take it twice a day.

KIRK HAMILTON: Or with meals or without?

DR. ARUN SANYAL: It probably does not make that much of a difference. It probably would get absorbed, because it is a fat soluble vitamin you need bile acids to absorb it. So you will probably do better if you take it in the context of meals. You might get better - at least there's a theoretical rationale for taking it with meals.

KIRK HAMILTON: These individuals - did you document whether they were vitamin E insufficient or not or blood levels of vitamins?

DR. ARUN SANYAL: Yes, we - that's a very good question. We actually look at that and they were not vitamin E deficient. They all had normal levels of vitamin E going into the study.

KIRK HAMILTON: Now let's talk about toxicity because there's people would think that that was a very high dose of vitamin E and it could be toxic and how would you answer that?

DR. ARUN SANYAL: There has been one particular meta-analysis which suggested that high dose vitamin E is increased with an increase in all cause mortality and there have been some other papers suggesting there might be a signal with respect to increased cardiovascular risks. So the way I think about it is as follows: Most of those studies, particularly the meta-analysis that was published in the Annals of Internal Medicine by Dr. Miller, vitamin E was being used for a variety of reasons but they were not really being used to treat a disease. They were being taken as health supplements in those studies. And the populations were incredibly varied from you know nursing home populations to people on dialysis to everything in between. The confounders on those studies are many and for example the smoking behavior, the use of other compounds, these were not quite well documented. At least in one of the studies in that meta-analysis patients were also taking very high doses of zinc which can make you copper deficient and set you up for oxidative stress and a variety of other problems. There was another study where patients were also getting high doses of vitamin A for which again there is some issue about possibility of toxicity. So the possibility of all these confounders was not really addressed because these are all retrospectively done reviews. In addition, there have been several large studies including one published in the JAMA in the last year or two looking at over 40,000 patients where they could not find any evidence that vitamin E increased all cause mortality and there was even a signal that it might improve cardiovascular outcomes in certain subpopulations, although personally I am very leery of post-hoc analyses. So the best I can tell the jury is still out, but even if it does have an effect, the absolute effect is actually relatively small because having looked at all these thousands of patients in all these different studies something else should have, you know, if there was a clinically significant effect that would have jumped out. Then there is a big difference between taking vitamin E as a health supplement because you want to live longer, which we know it doesn't really help you do that, versus taking it as a treatment of a disease which is associated with a significant morbidity and mortality. So NASH left alone will progress to cirrhosis in about 15 to 20% of people. Once you develop cirrhosis, your liver will decompensate at the rate of about 4% per year. There's a risk of developing liver cancer, and if you can reverse this disease with a treatment, then I think that's beneficial. So if you weigh on the one side the uncertain effect of all cause - on all cause mortality, and the likelihood that the absolute effect size, even if there is something which is very - the absolute effect is relatively small. And then on the other side the risk of leaving NASH untreated, I think you can make a rationale for using this dose of vitamin E for the treatment of NASH. Now having said all of this, I would put in the caveat that we have not established the benefit of NASH in a diabetic population or in people who have already developed cirrhosis and anytime we put a patient on high dose vitamin E, given that there is some controversy, it behooves us to closely monitor their cardiovascular risk profile and take steps to optimize that profile as best as we can.

KIRK HAMILTON: There's two things that you brought up in my mind. One is when you talked about mitochondrial function as being potentially dysfunctional or inhibited by a fatty liver or the NASH. Then why would you not consider things that have been used like coenzyme Q10, L-carnitine and ribose which actually help the energetics in cells as a potential treatment?

DR. ARUN SANYAL: That's an excellent question and I think there is a rationale for using those compounds, particularly coenzyme Q, but the studies need to be done and you know the - their actual clinical benefit needs to be documented before a recommendation can be made. But yes, there is a rationale for using something like this. Now what happens with the mitochondria, I will tell you is that in NASH, there is a structural defect in the mitochondria. So the mitochondrial structure falls apart and because of that, you get a failure of the normal electrochemical potential difference across the mitochondrial membrane which is critical for the mitochondria to generate ATP. So essentially what is required is one intervention before you have depleted all the mitochondrial DNA and before the enzymes of the mitochondrial respiratory chain are all depressed. Because you have an uncoupling between the mitochondria's ability to oxidize fatty acids and generate ATP. So you know all patients with NASH are not the same. And that's just my personal view. I think early in the course of fatty liver disease you have increased fatty acid oxidation. Because of the oxidative stress that is produced you damage the mitochondrial DNA and the mitochondrial DNA encodes for several components of the respiratory chain enzymes on the mitochondrial membranes which are responsible for converting the energy from burning fat into ATP. As you start losing all of this, your mitochondrial structure starts falling apart. You essentially have you know dysfunctional mitochondria. And so to recover from that you have - if you want to just catch it at a stage before the structural injury to the mitochondria, you have to get the antioxidants right in there to prevent the oxidative injury to the mitochondrial DNA. On the other hand if already damage has occurred, then you may need a product that not only shuts the process of injury down, but you have then you have to stimulate mitochondrial biogenesis.

KIRK HAMILTON: Do you know of a product?

DR. ARUN SANYAL: Ask me in a couple of years.

KIRK HAMILTON: Okay.

DR. ARUN SANYAL: Actually there are transcriptional factors which are known to regulate mitochondrial biogenesis, so it is an area of great research interest at this time for a variety - a number of people in the field.

KIRK HAMILTON: These are probably similar nutraceuticals that might be kind of a similar approach, but not quite the same. N-acetylcysteine is used for acetaminophen overdose to make I think endogenous glutathione in the liver to protect it.

DR. ARUN SANYAL: Correct.

KIRK HAMILTON: And so that would that not be a reasonable thing as well as something like alpha lipoic acid which -

DR. ARUN SANYAL: Yes, these all have rationale. N-acetylcysteine, you know, you'll smell like rotten eggs all day long, but other than that - no, I'm kidding - it's actually - it's - there is a theoretical rationale for all of these. But as you know with N-acetylcysteine especially if you take it orally you get really bad breath. When you're talking about using it as a drug for people who are relatively asymptomatic, remember most people have silent disease. To take a drug that will give them bad breath on a regular basis the likelihood of compliance is poor so we need a better way of improving intracellular glutathione stores. I agree with you. I think glutathione is very important. And not only that, probably the mitochondrial glutathione I suspect not having glutathione in the cytoplasm is important but it's really the mitochondrial glutathione which I think is going to be particularly important.

KIRK HAMILTON: Well I'm going to wrap this up, but I thank you and you gave a great explanation. One of the things that seems to me that just rings true to me that if you're eating a whole food unprocessed diet predominantly plant-based, and you're lean and active, that you're gonna -

DR. ARUN SANYAL: Chances are you're not going to get this disease.

KIRK HAMILTON: That's correct. I mean, I'm talking about nutrients as nutraceuticals but to me this is a lifestyle disease in my head, I mean first.

DR. ARUN SANYAL: To a large degree. Yes.

KIRK HAMILTON: Well I think this is - it's brought to the attention that this is an issue and it helps me actually as a practitioner. I mean I'm pretty aware of it, but it helps me look at it a little differently and a little more, next time I see elevated liver enzymes, it'll make me think a little harder.

DR. ARUN SANYAL: Good.

KIRK HAMILTON: Alright. Thank you so much Dr. Sanyal.

DR. ARUN SANYAL: Oh you're very welcome. Thank you.

KIRK HAMILTON: And I want to thank you, the audience, for this edition of Staying Health Today Radio. And until next time, Stay and Be Well.

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