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Sunday 30 September 2012

Dining In The Fourth Dimension

Dining in the Fourth Dimension

Remember when your parents or grandparents warned you against snacking and told you to wait till mealtimes? It turns out they were right, and that when you eat is almost as important as what you eat when it comes to the effect on your health.
Eating in time-restricted windows, or intermittent fasting, is proving to be a powerful tool for clearing liver fat, normalizing blood sugar, and improving energy. It costs nothing and does not involve eating less.
Even grazing animals don’t eat at night, and humans aren’t designed to graze. We have a gall bladder, which is an adaptation for digesting big fatty meals. A crocodile has a gall bladder, and it doesn’t eat every day.
It used to be thought that snacking brought us closer to the hunter-gatherer lifestyle. It was assumed that if you hunted and gathered all through the day, you’d eat as you went. The people who thought that had never lived with hunter-gatherers, and had forgotten about the importance of cooking and food preparation in their own lives. Hunting provides occasional kills, and gathered food tends to be collected to provide shared meals - such societies are co-operative and highly social. One or two large meals a day is the norm, not constant nibbling.
Experiments in humans and animals have confirmed that fitting one’s eating into a regular “window” improves markers such as liver fat, blood lipids, blood sugar control, and inflammation.
Mice get fat easiest on a high-fat diet, the way humans get fat on refined-carbohydrate diets. When mice were fed the same fattening diet, but only allowed to eat during an 8-hour window every day, they gained significantly less weight than mice that ate the same amount, of the same fattening food, but had had access to it round-the-clock. Better still, they even out-performed mice that had been fed a “healthy” diet (for mice) but had had access to it 24-7.
Two things seem to have contributed to this result: the 16-hour periods between meals when no food was entering the bloodstream allowed the body to go into “fasting” mode and use up stored fat, and generally sort out its energy arrangements (just as closing a supermarket at night makes it easier for staff to restock the shelves and clear up any mess); and the daily rhythm of hormone regulation became more defined. This is particularly relevant to hepatitis C as “brain fog” fatigue, insomnia and depression can be due to abnormal levels of cortisol, melatonin, serotonin and other hormones, the rise and fall of which should follow a daily pattern. The improvement in liver fat in the IF mice was also highly desirable.
I recommend eating between 10am and 6pm to “reset the body clock” in this way.
There are other variations but this one is least stressful to adapt to and works for me.
Intermittent fasting is the icing on the cake, and not the place to start with a Hep C diet. Begin with supplements and herbs, removing food toxins, restricting carbohydrate, before experimenting with IF.

Saturday 22 September 2012

More Cholesterol Madness; Malcolm Kendrick on Viral Hepatitis. Plus, What would Jesus eat?

The following is from an article by Malcolm Kendrick, author of The Great Cholesterol Myth.

And so the latest argument is that nobody in modern society has a normal cholesterol level. 
An article in the Journal of the American College of Cardiologybest sums up this line of thinking. Under the heading 'Why average is not normal', O'Keefe, the lead author, makes the claim that: 'Atherosclerosis is endemic in our population, in part because the average LDL ("bad" cholesterol) level is approximately twice the normal physiologic level.' In short, according to O'Keefe, our cholesterol level should be about 2.5mmol/l, not 5.2mmol/l.
This argument, if true, does neatly demolish the question 'How can people with normal, or low, cholesterol levels be protected against heart disease?'. O'Keefe and others would argue that we all have a high cholesterol level. Everyone is ill, and all shall have statins.
One regularly quoted fact, which superficially seems supportive of O'Keefe's hypothesis, is that peasant farmers in China have very low cholesterol levels and a very low rate of heart disease (although their average cholesterol levels are actually about four, not two-and-a-half).
But when you study the figures with more care, they reveal something else. As usual, those with low cholesterol levels have by far the highest mortality rates. Liver failure and liver cancer are common causes of death. However, there is a simple explanation for this association. Many Chinese peasant farmers have chronic hepatitis, which creates low cholesterol levels, and also leads to liver failure and liver cancer. This is why people with low cholesterol levels die young. 
Does this mean that a low cholesterol level protects against heart disease? No: what the Chinese data tell us is that those with higher cholesterol levels are not chronic hepatitis carriers, so they live longer and have more chance of developing heart disease in old age. On the other hand, those with low cholesterol levels cannot die of heart disease, because they are already dead.
Without chasing too many mad arguments around, the simple fact is that everyone in the West does not have a raised cholesterol level. Repeated studies have shown that a perfectly normal, or healthy, cholesterol level lies between about four and six, and lowering it cannot protect against heart disease, otherwise we will have introduced a new concept into medical science: normal is unhealthy and must be treated.


Message; cholesterol that is normal or "high" (the old "normal") is a good thing if you have chronic viral hepatitis. And cholesterol in your diet will provide some of the protection you're lacking if serum cholesterol is low; but it probably won't elevate serum cholesterol. This is more likely with saturated fat in the diet. Polyunsaturated oils and spreads are likely to depress it further.
Dr. Robert Atkins noted (in "Dr Atkin's New Diet Revolution") that his diet - high in fat, very low in carbohydrate - tended to lower cholesterol in patients when it was very high (the "normal" range was more realistic in his day) and raise cholesterol towards the normal range when it was unusually low.

What to eat? Although I revere Dr Atkins, the diets in his books use far too much oil and processed food.
These are two versions of what I think is just about ideal.
by Dr Kurt Harris, and
by Paul and Shou-Ching Jaminet.
I recommend trying the lower end of carbohydrate consumption in either diet; but I also think it's OK to experiment with both higher carb and ketogenic dieting to find out what's ideal for you.The supplements/ special nutrient suggestions in the Perfect Health Diet are valuable too, and if you want recipes The Perfect Health diet blog provides many examples.
Niether diet mentions Hep  C, but that's OK; we're not metabolic freaks, and in this case what's good for so many other people out there with type 2 diabetes, fatty liver, autoimmune problems, and malnutrition seems to be made for us.

In terms of a fasting lipid profile, there are some variables that may matter with regard to Hep C; you want TG (fasting tryglycerides) to be low (lower than HDL, or much the same, is perfect), and you do not want LDL or total cholesterol to be low.
High TG means that more HCV virions can leave the infected cells (estimated to average 50 per cell per day), low LDL means that they have more chance of getting into uninfected cells (because there are more receptors). Lower TG with any given LDL count means that the LDL particles are larger and there are fewer of them, which also reduces HCV virion opportunity. Low LDL may to some extent be compensated by a cholesterol-rich diet, which also reduces LDL receptor numbers.

"in experimental animals such as the hamster and the rabbit, dietary cholesterol increases liver cellular cholesterol and suppresses both hepatic cholesterol synthesis and LDL-receptor expression. In the rat, dietary cholesterol also increases liver cellular cholesterol, but its effect on the LDL-receptor is variable and species-dependent."

referenced in "Dietary Fats and Alcoholic Liver Disease" by Esteban Mezey:

Tuesday 18 September 2012

Vitamin D3 could save your life, pretty much.

What we have here is the full-text of a very good review paper on vitamin D and liver disease, including chronic Hep C, on the Hepatitis C Research and News blog.
The review is from the latest Journal of Hepatology.
This is good stuff, very thorough, and lacking the usual "vitamin D can be toxic, so you should be too scared to take our advice" hand-wringing that usually weakens the message when it trickles down to the Hep C community through the usual suspects.
All the fat-soluble vitamins are critical for surviving viral hepatitis, especially retinol, D3 and K2 (sourcing extra vitamin E in the diet is less important if the dietary fats are relatively saturated, but tocopherols and tocotrienols may be useful as part of an antioxidant regime). Selenium - a mineral needed to prevent peroxidation of fats - and carotenoids, which require fats for absorption, are also protective factors, but carotenoids are not a substitute for retinol.

See Plasma Selenium Levels and Risk of Hepatocellular Carcinoma among Men with Chronic Hepatitis Virus Infection for some population data on selenium, retinol and carotenoids. Although tocopherol - vitamin E - made no impression in these stats, the best dietary sources of tocopherol are exactly the oils high in linoleic acid - vegetable omega 6 - that promote liver fibrosis; so there may yet be a protective effect of tocopherol that is cancelled out by the context of the foods that are supplying it in this study. Vitamin E is necessary for maximizing the conversion of carotenoids to retinol.
Vitamin K2:

Monday 10 September 2012

How To Come Off Methadone Without Really Trying

Over a year ago - I think it was in August - I finally came off methadone, which drug I'd been taking since  the late 1980s, including every day, barring accidents, since 1990. I started reducing gradually from 120mg  in 2004, after I started taking antioxidants (see the recent post on Viral Manipulation of Host Behaviour).  There are two rules about this kind of slow reduction:

 The first: whatever happens, NEVER ask for the dose to be put back up. There's always something else you could be doing instead.

 The second rule is related to the first: use the discomfort from reductions to experiment, to sort out the changes in diet and lifestyle and the supplements that will actually help you once drug-free. At this stage there will always be another dose tomorrow, so mistakes are less important.

 By the end I had a pretty perfect protocol worked out. Diet really helped. Gluten, dairy, carbs, even too much fruit or vege made things much harder. This is the letter I wrote to my case manager when I quit. I was on about 7.5 mg/day and could have drawn it out longer. Some people say the last drop is the hardest, but this wasn't the case with me. Every drop got easier and easier. The less methadone I took, the better I felt. I still have my last doses of methadone in the house. In the past year I've never considered I've had any use for it, nor have I felt any kind of desire for it. Feelin' fine...

15 August 2011

Hi Mark,
I won't require another pickup, I'm due for one tomorrow, but don't need it, having had no dose since Friday. Saturday I was weak and slept very badly, Sunday I was weaker but slept well, today I feel virtually normal if a bit convalescent. Unless my body has found and
 released a stored well of methadone, I think I'm over the worst.

 As I have got lower adjustement has tended to get faster.

 My tips for withdrawal; 

1) low carb diet. Cravings for unhealthy (sweet or high-carb) food and cravings for drugs are related, so a diet that reduces cravings of all sorts is best. Plus, I think it easier and more reliable to burn fat than carbohydrate during withdrawal. And extra protein is required - make room for it.

2) hormonal regulation - supplement vitamin D, use DLPA pre-treatment to elevate endorphins during withdrawal, tribulus increases hardihood and resistance to pain and stress.

3) l-carnitine or acetylcarnitine is clinically proven to significantly reduce methadone withdrawal; 500mg 3-4x daily improves energy and mental focus by promoting burning of fats and GABA sensitivity. 

4) niacin (as niacin 100-200mg PRN or no-flush niacin 500mg 3-4xdaily) supresses craving and physical discomfort, especially combined with vitamin C.

5) magnesium chelate in high doses, plus salt, prevents cramps

6) high-dose probiotic prevents diarrhoea

7) multivitamin/mineral because metabolism is sped up, diuresis etc. will deplete some other nutrients. Not so much on a nutrient-dense low-carb diet though.

I was following this regime through the lower stages, below 10mg.

And there you have it. Feelin' fine, and no struggle over willpower 
(whatever that is) was ever required, methadone (and other drugs) held no appeal, but an inspiring dream on Friday night definitely helped.

In my dream I was looking at pictures of cities;
 one was: Dunedin: the Edinburgh of the Antarctic. the other: Edinburgh: the Edinburgh of the World. 

Then I was on a skyscraper over Edinburgh (the city where I was born) looking down on huge cathedrals and mausoleums, around to skyscrapers, then up and around to structures built by Gods or Giants, in a kind of Art Deco style, topped by square white pillars with a rounded edge at the front topped by statues of winged Egyptian animal-headed Gods which I could see all around the skyline, all visible in a bright, pastel light like the light of sunrise, or a Maxfield Parrish sky. Then I realised how high up I was, how dangerous it was to get back inside, and woke up. The awe-struck emotion from the dream and the imagery remained with me vividly all day. An experience of grandeur as an intense emotion. What it meant I can't say but it sure was a good thing.

Footnote: at a time of stress you need lots of energy, but you also don't want too much food that needs digesting sitting your stomach. A diet that helps you burn any stored fat (i.e. a diet that doesn't raise insulin) and that also supplies concentrated energy - i.e. is "energy dense" in the language of the Food Police - is one that adds less stress to an already stressful situation.

See this very different yet weirdly analogous story about running an ultra marathon on a low-carb diet:
You  can learn a lot about low-carb vs. high carb from a careful perusal of this story, even if you're not interested in athletics. For example, it becomes obvious why people who are dieting tend to eat fewer calories on high-fat diets. It has nothing to do with flavour.

He’s got very little body fat, but if let’s say he’s 7% by weight body fat that means he still has at least 30,000 calories of fat in his body when he starts the race.

A 30,000 calorie tank of fuel?  On his body?
STEVE PHINNEY:  When the starting gun goes off, 30,000 calories of body fat.  Now, if you run this race typically your body will burn 10,000 calories over the 100-mile course, so he’s got enough to run the race three times over before runs out of fat fuel.  But that’s because he’s a fat-burner.  For the carb loaded runners, who are less adapted to burning fat, at the same starting line, even if they’d done their carb loading to the maximum, the most carb calories they’d have in their bodies is 2,000.  Now, if you’re running on a carb fuel strategy, and you’ll need 10,000 calories to complete the 100-mile race, that 2,000 calories of carb stored in your body at the start of the race is only 1/5 of the fuel that you need to complete the race.

High-carbers have to fuel up more often?
STEVE PHINNEY:  That’s correct.  In contrast, if you’re running on a fat fuel strategy, you’ve got three times as much fuel in the tank as you need to complete the race and that’s the beauty, literally the metabolic beauty of the low-carb adapted athlete in an ultra-performance event.

That leads to another important distinction between the high carb diet high-fat diet and that is for many runners when they use the high carbohydrate fuel strategy many runners found that by mile 50 and certainly by mile 75 that they started having major gastrointestinal upset.  The upset would get to the point that not only could they not hold food  down, but they had a hard time holding liquids down.

Some high-carb runners had trouble with digestion?  But not on low-carb/high fat?
STEVE PHINNEY: Yes, and that’s disastrous in a race where the sweat losses and the evaporative losses are so great that if you can’t keep fluids coming in, you’re out of the race.  Many of the high-carbohydrate runners experienced frequent and severe gastrointestinal problems.  In fact, what has induced many of them to do this bold thing and switch to get being low-carb is that they’ve heard from other people who do this race that when they went from high carb to a low-carb, high-fat diet those gastrointestinal problems went away.

Now, if you were just detoxing off opiates, instead of running an ultra-marathon, that would still be a highly desirable advantage, wouldn't it?

Friday 7 September 2012

Preventing and Reversing Hepatic Fibrosis - Herbs and Supplements

Limitations of the paper: This was written a few years ago and does not incorporate everything I have learned since. Nor does it contain many references and live links, though I have added some, and some references do appear at the end. It is obviously unfinished - a work in progress posted to inspire other researchers - and should be treated as such.
On the other hand it compiles much valuable information that does not appear elsewhere.

A reference first to set the scene:

Hepatology 2006 Feb;43(2 Suppl 1):S82-8.

Reversal of hepatic fibrosis -- fact or fantasy?

Friedman SL, Bansal MB.

Realistic expectations for successful anti-fibrotic therapies reflect solid evidence of fibrosis 

regression in patients treated effectively for viral liver disease, as well as growing clarity in 

the understanding of mechanisms of extracellular matrix production and degradation. 

The paradigms of stellate cell activation and apoptosis remain valuable frameworks for 

understanding pathways of hepatic fibrogenesis and fibrosis regression, respectively.

Liver Fibrosis - Prevention and Reversal

Hepatic stellate cell activation and proliferation; HSC inhibition, apoptosis, and reversion induced by natural compounds.

The Hepatitis C Handbook by Matthew Dolan is one of the best resources in the subject of Hep C. I was amazed to find, looking up fibrosis in the index, that there is no reference at all to it in the 1997 edition.
Until the last 10 years or so fibrosis was seen purely as an aspect of liver damage that was not really distinct from damage to hepatocytes. In fact, fibrosis, and therefore cirrhosis is an aspect of liver repair mechanisms, albeit one that can lead towards increased damage and loss of function if it is not switched off. The good news is that many strategies have been developed to switch off fibrosis and resorb scarring (for example, in Modern Chinese Medicine the herbal preparation Cpd 861 was able to reverse 4 stages of fibrosis and 2 of cirrhosis in clinical trials) and it seems relatively easy to prevent fibrosis from snowballing in the first place. To understand how this is possible, we must first look at fibrosis as a natural event.

Hepatic Stellate Cells
Damage to the liver, whether by drugs, virus, radiation, or trauma (for example, a biopsy needle) must involve damage to the microcirculation, the tiny blood vessels essential to liver function, as well as to hepatocytes. The microcirculation consists of endothelial cells, called sinusoidal because there are windows in them. This tiny tube, only 2-3 cells in diameter, is surrounded by a space (the Space of Disse) separating it from the hepatocytes. The Space of Disse is inhabited by main two cell types; Kuppfer cells, the macrophage white blood cells that keep it clean, and Hepatic Stellate Cells (HSCs or Ito cells). In health, HSCs have three main functions; they store fats and vitamin A; they produce and degrade matrix (collagen and similar protein fibres), both to restrict the size of particles able to pass in and out of the microcirculation, and perhaps to keep open the Space of Disse; and, HSC also serve as glial cells, similar to the neuroglial caretaker cells in the brain; that is, they respond to many neurotransmitters and neural hormones, and can both break down and produce many such chemicals, interacting with the nerves that transit the liver. This is particularly important as it gives a mechanism as to how moods and emotions can impact on liver function, and vice versa, as well as some psychoactive drugs.

HSC activation
In the case of traumatic or chemical liver damage, the function of HSCs changes. They lose their vitamin A stores and convert to a type of cell called a myofibroblast. Fibroblasts are seen in scar formation in other tissues, and are part of the immune response to injury. The primary function of the HSC fibroblast is to remodel the damaged intracellular matrix (collagen), by breaking it down with zinc-containing metalloproteins (in healthy HSCs, zinc is used in the storage and transport of vitamin A instead) and creating more. HSC myofibroblasts also conscript other HSCs to their aid, by producing chemicals that spread the process of conversion (HSC activation) and reproduction (HSC proliferation). This process ought to be switched off once the liver has repaired itself, but in some cases does not stop, and this ongoing remodeling of matrix collagen results in the later stages of fibrosis, and cirrhosis; the HSC fibroblasts produce tangles of collagen and also contract around the endothelial cells, closing down the (already microscopically narrow) blood vessels of the microcirculation and causing toxins to accumulate, and the hepatocytes in the area lose their function, eventually dying and setting off another cycle of fibrosis.

Nitric Oxide
An important chemical messenger for keeping HSCs in line and maintaining the tone of the microcirculation is endothelial nitric oxide (NO.-). Nitric oxide is a free radical that functions, in the liver, as an antioxidant; other free radicals, such as superoxide, can destroy it. For this reason antioxidants help to maintain nitric oxide levels, for example Ginkgo. Preparations of antifibrotic herbs based on Ginkgo extracts have successfully prevented fibrosis in clinical trials. I will discus the mechanism and success rates of other antifibrotic herbs later. Nitric oxide is produced from the interaction of l-arginine and oxygen, catalysed by NADPH, a vitamin B3 co-enzyme. Vitamin B3 (as niacinamide) also has important antifibrotic effects in its own right.

Inflammatory Cytokines and Niacinamide/Nicotinamide
The primary cytokines (protein messengers) involved in activating HSCs are Transforming Growth Factor Beta (TGF–beta) and TNF-alpha, which activates the pro-inflammatory transcription factor NF-kappaB. Vitamin B3 as nicotinamide inhibits both TGF-beta and TNF-alpha. Vitamin E, especially in the form of alpha-tocopherol succinate, also inhibits TNF-alpha and NF-kappa B. We know that these vitamins are effective at normal supplement doses because vitamin B3 is effective against arthritis, which is another disease in which TNF-alpha and NF-kappa B play a major role, at doses which (at the upper end) can affect liver function in other ways, by competing for SAMe, thus inhibiting the transport of fats from hepatocytes (potentially leading to jaundice in poorly nourished individuals with hypomethylation – easily prevented by taking B12 and folate, and by taking divided doses, rather than taking one large dose. However in clinical use manifestation of these potential risks is minimal). B3 also elevates HDL cholesterol, and higher levels of HDL cholesterol are associated with healthy nitric oxide levels.
The most important effect of B3 is, that it induces the apoptosis (programmed cell death) of activated HSCs. B3 is the only vitamin that does this. Apoptosis of HSCs, as well as quiescence, is probably essential if the liver is to recover from fibrosis. Other supplements that promote HSC apoptosis are CLA (conjugated lineolic acid) especially the c-9, t-11 isomer found in ruminant and dairy fat, resveratrol (which likely promotes HCV replication in high doses), green tea extract, apricot kernels, and berberine (an alkaloid found in many yellow herbs, including golden seal, coptis, and Oregon grape root).

HSCs are also activated by some neurotransmitters at high concentrations, including serotonin, epinephrine (adrenaline), and adenosine. Caffeine inhibits adenosine receptors; it also increases synthesis of nitric oxide and lessens synthesis of collagen precursors from l-arginine, while the antioxidant polyphenols in coffee chelate iron and protect nitric oxide and collagen; this is probably related to the anti-fibrotic effects seen in some coffee drinkers (antioxidants that protect collagen, such as OPCs, tend to be anti-fibrotic; it makes sense that damage to matrix should trigger HSC activation). A neurotransmitter which inhibits HSC activation is gamma butyric acid, GABA. Vitamin B3 enhances sensitivity of GABA receptors – in fact, this gives it an anti-anxiety effect equal to that of valium, as GABA is an inhibitory neurotransmitter, opposed to adrenaline which is stimulatory, and valium has an antianxiety effect in part because it attaches itself to GABA receptors. This is another antifibrotic mechanism of niacinamide. It would be interesting to see whether this GABA-ligand effect translates into any antifibrotic influence for benzodiazepine drug use. However, the antifibrotic effects of B3 which I have researched are multiple, and do not depend on any single mechanism. They include:
synthesis of nitric oxide - increase of nitric oxide by inhibition of ADMA - increase of HDL cholesterol - reduction (recycling) of glutathione - modulation of GABA receptors -  inhibition of TNF-alpha and NF-kappaB - inhibition of TGF-beta - inhibition of HSC activation and proliferation - promotion of HSC apoptosis prevention of excess catecholamine synthesis - lowered synthesis of acetaldehyde from alcohol, therefore less toxicity.
Benefits of B3 supplementation in fibrosis, not limited to those above, strongly suggest that commonly repeated advice to avoid this vitamin in cases of hepatitis is misguided. Jaundice and acute hepatitis are contraindications, and daily dose then should be limited to 200mg in multivitamins, but in stable, chronic  cases of hepatitis C a dose of 500mg niacinamide 3x daily seems well tolerated. The only toxicity of B3 relates to its methyl-acceptor role; as long as one supplements B12 and folate, or SAMe, or lecithin, and eats a reasonable amount of protein, this will not cause hypomethylation. Niacinamide (with other vitamins) has been used for decades in the orthomloecular treatment of alcoholism, with prevention of cirrhosis as an incidental benefit, without serious complications, despite the prevelance of liver damage in alcoholics. 

Estrogen, antifibrotic foods
Estrogen is also antifibrotic, and pre-menopausal women have a lower rate of fibrosis than males. However, this protection can be lost at menopause. However, phytoestrogens, especially genistein from soy, also inhibit HSC activation and proliferation by acting on estrogen-B receptors. On the n=1, I am allergic to unfermented soy, and I don’t consider it a fit food for humans, but I have no problems with isoflavones, which are found in a variety of legumes. Fermented soy products are a better source of isoflavones than unfermented. Resveratrol is another phytoestrogen effective at dietary levels; grape juice and raisins supply as much resveratrol as red wine.
Another food that is antifibrotic at normal dietary levels is curry. Both curcumin (from turmeric) and extract of fenugreek (methi) inhibit HSC activation. India has a high rate of hepatitis C infection yet a low rate of liver cancer (a rare sequella of fibrosis), and this has been attributed to the consumption of curries. Other ingredients in curry, including saffron, have been studied for their antifibrotic effect. The use of ghee, high in saturated fat and CLA, in the traditional Indian diet is also likely to provide antifibrotic benefits.

Iron, unless it is strongly bound in proteins or chelated with polyphenolic phytochemicals, is strongly pro-fibrotic and all antifibrotic herbal extracts and phytochemicals seem to have some iron-chelating ability. Iron interacts with superoxide (Haber-Weiss reaction) and peroxide radicals (Fenton reaction) to produce the more reactive hydroxyl radical (also the product of ionizing radiation – both nuclear and electromagnetic). Iron can also interact with antioxidant vitamins, especially vitamin C, in place of superoxide, and iron-vitamin C combinations are used to induce fibrosis (activate HSCs) experimentally. Thus, taking vitamin supplements that combine vitamin C and inorganic iron in one pill is rather unwise – but avoiding vitamin C will not help. Firstly, the same kind of reaction takes place with superoxide radical, which is more reactive than any antioxidant (and more penetrative), as well as with glucose and homocysteine (pro-fibrotic in its own right), and superoxide (as well as glucose and homocysteine) levels will be higher if antioxidants are low; secondly, vitamin C deficiency causes the formation of low-quality collagen, which might be a factor in the constant matrix remodelling seen in fibrosis; thirdly, ascorbate-iron catalyzed hydroxylation reactions play an important role in metabolism and detoxification; the synthesis of carnitine, tyrosine and serotonin, for example, depends on this type of reaction.

Copper can also function in the same way. Zinc, which is important for the breakdown of matrix collagen, competes for absorption with iron and copper (especially as inorganic zinc sulphate – note that organic mineral chelates may not compete asa directly). Calcium also competes with iron, as do many phytochemicals, including coffee and green and black teas.

Antioxidant Enzymes
But iron can become very strongly antioxidant if it is part of the catalase enzyme, which converts peroxide to water (similar to the selenium-containing enzyme glutathione peroxidase). Catalase works together with SOD (copper and zinc, or manganese) to remove superoxide and peroxide before they can react with reduced iron (Fe2+). Adaptogenic medicinal herbs like ginseng and astragalus and medicinal mushrooms are able to increase production of these enzymes (assuming the minerals – especially selenium, zinc, and manganese, as iron and copper are usually found elevated in Hep C - are there), as do the isothiocyanates and glucosinolates found in cruciferous vegetables (broccoli, cabbage, kale, watercress, mustard etc.).

Vitamin A
Because HSCs naturally store vitamin A, it might be expected that vitamin A would have some action for or against fibrosis. It turns out that vitamin A as retinyl palmitate (the form of vitamin A in cod liver oil) is potently antifibrotic (as are various carotenoids in their own right), but a very interesting feature of this in animal trials is that liver pretreated with vitamin A and exposed to toxicity produces less collagen and fewer activated HSCs than liver not so pretreated, yet the vitamin A pretreated liver has a significantly higher level of AST and ALT liver enzymes after the toxic exposure. In other words, an elevated liver enzyme count can be consistent with the prevention of fibrosis.
No doubt damaged hepatocytes can be replaced more easily than excess collagen can be cleared away. In the MCM medicines below, hepatoprotective herbs (such as schizandra) are sometimes added to antifibrotic mixtures.

Vitamin D is also anti-fibrotic
The non-scientific literature on Hep C is full of warnings against supplementing nicotinamide, retinol, and vitamin D3.
These warnings, based on the effects of extreme overdose, have no relevance to normal diet or supplementation at clinical dosages. Restricting these vitamins in the belief that they are dangerous is infinitely more risky than supplementing them. Retinol status, for example, is inversely associated with hepatocellular cancer in prospective studies of populations with chronic viral hepatitis.

Modern Chinese Medicine
Modern Chinese Medicine has made a special study of fibrosis, identifying both the processes involved and a number of traditional herbs that address various aspects of fibrosis, especially when associated with viral hepatitis. Herbal mixtures have been designed to address various aspects of fibrosis prevention in one formula. Thus apricot kernels (armand de nord, north almonds, bitter almonds), which promote HSC apoptosis, may be combined with pine pollen, which protects collagen and microcirculation, cordyceps, a medicinal mushroom with antiviral properties which corrects immune suppression, ligusticum, which reduces platelet stickiness (PAF, platelet aggregating factor, is a factor in fibrosis), notoginseng, which is a potent antioxidant with traditional use in protecting the cardiac circulation, and schizandra, which protects hepatocytes and increases bile flow. The star of antifibrotic herbs in MCM seems to be the very well researched radix salvia miltiorrhiza (red sage, dan shen), a cheap herb with multiple antifibrotic actions. Salvia out-performs other herbs and polyphenols with antifibrotic actions, at levels easily attained by supplementation with extracts, and is used in most MCM antifibrotic mixtures.
Reversal of fibrosis and even early-stage cirrhosis is often seen in clinical trials of these new Chinese medicines. I predict that the rate of reversal will increase when the herbs are combined with appropriate amounts of antioxidant and antifibrotic nutrients; a-tocopherol succinate, selenium, zinc, manganese, niacinamide, NAC, lecithin, cod liver oil, OPCs, as well as antifibrotic foods; curries, grapes and raisins, mango, berries, soy and other legumes. The neuroglial function of HSCs provides scientific validation for stress-relieving practices such as breathing excercises, yoga, tai chi, and cognitive therapy in the management of fibrosis.

REFERENCES (to be expanded. In the meantime, to find a reference i.e. to the antifibrotic effect of curcumin, just google "curcumin hepatic stellate", and so forth. Medline references will then be found at the top of the next page.)

1    Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem
      2000; 275:2247-2250

2    Iredale JP. Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 2001; 21: 427-436

3    Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis
      2001; 21: 437-451

4    Reeves HL, Friedman SL. Activation of hepatic stellate cells -a key issue in liver fibrosis. Front Biosci 2002; 7: d808-826

    Wang BE, Wang TL, Jia JD, Ma H, Duan ZP, Li XM, Li J, Wang AM, Qian LX. Experiment and clinical study on inhibition
      and reversion of liver fibrosis with integrated Chinese and Western Medicine. CJIM 1999; 5: 6-11

    Yin SS, Wang BE, Wang TL. The effect of Cpd 861 on chronic hepatitis B related fibrosis and early cirrhosis: A
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      on HBV -related liver fibrosis with herbal compound 861. Weichangbingxue He Ganbingxue Zazhi 1998; 7: 148-153

Saturday 1 September 2012

A Hard Day's Night - Cholesterol, Cancer and Selenium

Note: this is a long post, but stay with me; it has some surprising twists. Tell your friends, but don't spoil the ending for them!

Low cholesterol is a risk factor for liver cancer in HBV infection; I wouldn't be surprised if it's the same for HCV, as low cholesterol is a risk factor for fibrosis and non-response.


BMJ. 1993 Apr 3;306(6882):890-4.

Prolonged infection with hepatitis B virus and association between low blood cholesterol concentration and liver cancer.

Chen Z, Keech A, Collins R, Slavin B, Chen J, Campbell TC, Peto R.

OBJECTIVE: To determine whether prolonged infection with hepatitis B virus is associated with a lower blood cholesterol concentration.

DESIGN: Cross sectional study.

SETTING: 81 villages in rural China with a high prevalence of chronic infection with hepatitis B virus.

SUBJECTS: 1556 apparently healthy men aged 35-64 years, randomly selected.

MAIN OUTCOME MEASURES: Hepatitis B virus carrier state; plasma concentrations of cholesterol, apolipoprotein B, and apolipoprotein A I.

RESULTS: 238 (15%) of the men were positive for hepatitis B surface antigen, indicating that they were chronic carriers. Plasma concentration of cholesterol was 4.2% (0.11 mmol/l) lower among carriers (that is, positive for hepatitis B surface antigen) than among non-carriers (95% confidence interval 0.6% to 8.0% (0.01 to 0.21 mmol/l), p < 0.05), and apolipoprotein B concentration was 7.0% (0.036 g/l) lower (2.8% to 11.2% (0.014 to 0.058 g/l), p < 0.001). In contrast, no association was observed between plasma concentrations of cholesterol or apolipoprotein and hepatitis B that had been eradicated (that is, patient positive for hepatitis B core antibody but negative for hepatitis B surface antigen).

CONCLUSIONS: Chronic hepatitis B virus infection, which usually starts in early childhood in China, seems to lead not only to a greatly increased risk of death from liver disease but also to a somewhat lower cholesterol concentration in adulthood. This common cause produces an inverse association between cholesterol concentration and risk of death from liver cancer or from other chronic liver diseases.

Much the same thing happens with Hep C, where low cholesterol is definitely a part of the viral strategy, not just a consequence of liver damage:

J Viral Hepat. 2006 Jan;13(1):56-61.

Serum lipid pattern in chronic hepatitis C: histological and virological correlations.

Siagris D, Christofidou M, Theocharis GJ, Pagoni N, Papadimitriou C, Lekkou A, Thomopoulos K, Starakis I, Tsamandas AC, Labropoulou-Karatza C.

Lipoproteins are closely connected to the process of hepatitis C virus (HCV) infection. The aim of this study was to evaluate the lipaemic profile in patients with chronic HCV infection, and to identify any association between serum lipid levels and viral load, HCV genotype or liver histology. Total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) were measured in the sera of 155 patients with chronic HCV infection and 138 normal subjects, matched for age and sex. Viral parameters and liver histology were evaluated in HCV-infected patients.

Serum TC (P < 0.0005), HDL-C (P < 0.0005) and LDL-C (P < 0.0005) were lower in chronic hepatitis C patients compared with controls. Grading score was positively correlated with TC and LDL-C. Patients with HCV genotype 3a had significantly lower levels of TC, HDL-C, LDL-C, higher viral load and higher frequency of hepatic steatosis than those with other genotypes. Logistic regression analysis identified genotype 3a (OR, 6.96; 95% CI, 2.17-22.32, P = 0.0011) as the only significant predictive variable associated with low serum cholesterol concentration.

HCV infection is associated with clinically significant lower cholesterol levels (TC, LDL and HDL) when compared with those of normal subjects. This finding is more pronounced in patients infected with HCV genotype 3a.[/b] Further studies are necessary to define the pathophysiology of the relationship between lipid metabolism and HCV infection.


And low cholesterol in Hep C is also associated with an increased risk of liver cancer:

HPB (Oxford). 2010 Nov;12(9):625-36. doi: 10.1111/j.1477-2574.2010.00207.x.

Evidence of aberrant lipid metabolism in hepatitis C and hepatocellular carcinoma.

Wu JM, Skill NJ, Maluccio MA.

OBJECTIVES: Lipids are linked to many pathological processes including hepatic steatosis and liver malignancy. This study aimed to explore lipid metabolism in hepatitis C virus (HCV) and HCV-related hepatocellular carcinoma (HCC).

METHODS: Serum lipids were measured in normal, HCV and HCV-HCC patients. Whole-genome microarray was performed to identify potential signature genes involved in lipid metabolism characterizing normal vs. HCV vs. HCV-HCC conditions.

RESULTS: Serum cholesterol was significantly reduced in HCV and HCV-HCC patients compared with normal controls, whereas there was no difference in glucose and triglycerides. Microarray analysis identified 224 probe sets with known functional roles in lipid metabolism (anova, 1.5-fold, P ≤ 0.001). Gene-mediated fatty acid (FA) de novo synthesis and uptake were upregulated in HCV and this upregulation was further enhanced in HCC. Genes involved in FA oxidation were downregulated in both the HCV and HCC groups**. The abnormality of cholesterol metabolism in HCV was associated with downregulation of genes involved in cholesterol biosynthesis, absorption and transportation and bile acid synthesis; this abnormality was further intensified in HCC.

CONCLUSIONS: Our data support the notion that HCV-related lipid metabolic abnormalities may contribute to hepatic steatosis and the development of cancer. Identification of these aberrations would stratify patients and improve treatment algorithms.


My conclusions;

dietary cholesterol ought to reverse some of these abnormalities; this would explain the strong protective effect of eggs against viral hepatitis mortality seen in the China Study (note that T C Campbell, author of the controversial China Study*, was one of the authors of the first paper).

Replacing seed oils with animal fats, polyunsaturated fats (other than those in animal fats - AA, EPA and DHA) with monounsaturated and saturated fats, and restricting carbohydrate, especially sugar and grains, will tend to correct HCV-related lipid abnormalities.

[* Controversial because T C Campbell is a vegetarian and misinterpreted some of the China study data selectively to support a vegan bias. Amongst other things, he misinterpreted the effects of a diet of pure casein - which is a selenium-deficient purified milk protein used to produce liver cancer experimentally in rats - to claim that all animal protein is somehow harmful, and vegetable protein is beneficial. For example, soy, gluten and peanuts - yeah right, I don't think so. We'll come back to selenium in a minute.]

**"Genes involved in FA oxidation were downregulated in both the HCV and HCC groups". Very low carbohydrate dieting (and/or fasting) reactivates these fat burning genes, such as PPAR-alpha, which also inhibits HCV replication (the naringenin gene).

Perhaps vitamin E is not very effective (below) because it fails to elevate cholesterol in HCV (it is usually supposed to "improve" lipids somewhat):


Int J Vitam Nutr Res. 2003 Nov;73(6):411-5.

Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.

Takagi H, Kakizaki S, Sohara N, Sato K, Tsukioka G, Tago Y, Konaka K, Kabeya K, Kaneko M, Takayama H, Hashimoto Y, Yamada T, Takahashi H, Shimojo H, Nagamine T, Mori M.

Patients with chronic hepatitis C virus (HCV) infection often develop liver cirrhosis and hepatocellular carcinoma (HCC). The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection.

Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at random into two groups. Forty-four patients were treated with alpha-tocopherol (Vit E group) while the other 39 were followed as controls. The clinical background (gender, age, and laboratory data) was similar in the two groups. Serum levels of alpha-tocopherol, albumin, alanine aminotransferase (ALT), and total cholesterol and platelet count were measured serially over a period of five years.

The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment. Platelet count, serum albumin, ALT, and total cholesterol were not different between the two groups during the five-year period. Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls, albeit statistically insignificant. The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV. Although the administration of alpha-tocopherol normalized the level one month later, it could neither improve liver function, suppress hepatocarcinogenesis, nor improve cumulative survival.

Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant.


You might remember how the Cochrane Collaboration did a meta-analysis of clinical trials of antioxidant supplements some years back and found most of them increased mortalitity? Apart from selenium and vitamin C, that is.

One finding of the Cochrane Collaboration was that selenium supplements (and only selenium supplements) significantly reduced the occurence of gastrointestinal cancers in all of five trials - an average relative risk of 0.59 (0.46-0.75).

I wonder, was liver cancer considered a GI cancer for the purposes of that analysis?


Nutrients. 2010 Sep;2(9):929-49. Epub 2010

Has Selenium a Chemopreventive Effect on Hepatocellular Carcinoma?

Both experimental and epidemiologic studies have linked a low dietary intake of selenium with an increased risk of cancer. The authors examined the association between plasma selenium levels and risk of hepatocellular carcionoma (HCC) among chronic carriers of hepatitis B and/or C virus in a cohort of 7, 342 men in Taiwan who were recruited by personal interview and blood draw during 1988–1992. After these men were followed up for an average of 5.3 years, selenium levels in the stored plasma were measured by using hydride atomic absorption spectrometry for 69 incident HCC cases who were positive for hepatitis B surface antigen (HBsAg) and/or antibodies against hepatitis C virus (mostly HBsAg positive) and 139 matched, healthy controls who were HBsAg positive. Mean selenium levels were significantly lower in the HCC cases than in the HBsAg-positive controls (p =0.01). Adjusted odds ratios of HCC for subjects in increasing quintiles of plasma selenium were 1.00, 0.52, 0.32, 0.19, and 0.62, respectively. The inverse association between plasma selenium levels and HCC was most striking among cigarette smokers and among subjects with low plasma levels of retinol or various carotenoids. There was no clear evidence for an interaction between selenium and α-tocopherol in relation to HCC risk.
Am J Epidemiol 1999; 150; 367–74.

Anticancer Agents Med Chem. 2010 May;10(4):338-45.

Selenium in the prevention and treatment of hepatocellular carcinoma.
Darvesh AS, Bishayee A.

Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed.


And now, for those who've made it this far, a real treat:

Our findings indicate that selenium deficiency induces apoptosis in some “hepatocyte-like” cells. However, most HCC cells, particularly HBV-related ones, tolerate selenium deficiency and escape its deadly consequences. Thus, as demonstrated by the gain of survival capacity of apoptosis-sensitive cell lines with Vitamin E, such malignant cells have acquired a selective survival advantage that is prominent under selenium-deficient and oxidative-stress conditions.


Hepatocellular cancer cell lines containing HBV virus genes are more resistant to selenium deficiency than other hepatocytes.

I'll bet that exactly the same thing applies to HCV. You won't get it in the genome like HBV as it's an RNA not a DNA virus, but there's the same relationship with selenium deficiency and cancer, so it seems likely.

Brazil nuts = 19mcg selenium each on average.

(Note: most if not all hepatocytes used in HCV cell culture studies are actually hepatoma - i.e. liver cancer - cell lines. Maybe that's why the antiviral drugs they develop don't always work in real livers! And maybe some of what we think we know about HCV is wrong.)

And the final twist, worthy of Roald Dahl:

First, some news from the UK;

Too Much Selenium Can Increase Your Cholesterol

The researchers found in those participants with higher plasma selenium (more than 1.20 µmol/L) there was an average total cholesterol level increase of 8% (0.39 mmol/L (i.e. 15.1 mg/dL). Researchers also noted a 10% increase in non-HDL cholesterol levels (lipoproteins within your total cholesterol that can help predict the risk of someone suffering a heart attack or chest pain). Also, of the participants with the highest selenium levels, 48.2% admitted they regularly took dietary supplements.

A 10% increase in what we might here term "good" cholesterol might be just enough to offset the drop in cholesterol caused by HCV.

(I like the way that 48.2% of these subjects "admitted" to taking supplements that may have elevated their non-HDL cholesterol. Not "reported", "admitted". No doubt they cracked under interrogation, while the other 51.8% successfully denied the allegation.)

US research shows the same trend;

Atherosclerosis. 2010 Jun;210(2):643-8. Epub 2010 Jan 11.

Serum selenium and serum lipids in US adults: National Health and Nutrition Examination Survey (NHANES) 2003-2004.

Laclaustra M, Stranges S, Navas-Acien A, Ordovas JM, Guallar E.

OBJECTIVE: High selenium has been recently associated with several cardiovascular and metabolic risk factors including diabetes, blood pressure and lipid levels. We evaluated the association of serum selenium with fasting serum lipid levels in the National Health and Nutrition Examination Survey (NHANES) 2003-2004, the most recently available representative sample of the US population that measured selenium levels.

METHODS: Cross-sectional analysis of 1159 adults>or=40 years old from NHANES 2003-2004. Serum selenium was measured by inductively coupled plasma-dynamic reaction cell-mass spectrometry. Fasting serum total cholesterol, triglycerides, and HDL cholesterol were measured enzymatically and LDL cholesterol was calculated.

RESULTS: Mean serum selenium was 136.7 microg/L.
[HTML's inconvenient but understandable dislike of epidemiological data presentations means that you'll have to look at the fulltext for details, sorry]

CONCLUSION: In US adults, high serum selenium concentrations were associated with increased serum concentrations of total and LDL cholesterol. Selenium was associated with increasing HDL cholesterol only at low selenium levels. Given increasing trends in dietary selenium intake and supplementation, the causal mechanisms underlying these associations need to be fully characterized.

full text here:


Of course, fatty animal foods - such as pork and bacon - are the best source of selenium besides brazil nuts and supplements, so some of these statistics could be due to the cholesterol-elevating effects of animal fats.

"of the participants with the highest selenium levels, 48.2% admitted they regularly took dietary supplements" in the UK study; it was 75.1% in the US, but surely not all supplements supplied selenium and even fewer supplied a high dose of selenium.

From table 1 the difference in saturated fat intake between quartiles is small but the trend matches selenium.

But still - there's a pattern here.

Enter the virus, cholesterol goes down, cancer goes up;

enter selenium, cholesterol goes up, cancer goes down.

Oh, by the way, lower cholesterol is associated with higher cancer death rates across the board...

This paper summarizes the state of research into selenium and seum lipids and glucose: 

"Interestingly, the effects of selenium supplementation on blood lipids are contradictory in animal and human studies. In rats, selenium supplementation increases LDL receptor activity [28,29] but decreases 3-hydroxy 3-methylglutaryl co-enzyme A (HMG-CoA) reductase expression [30], leading to decreased plasma LDL cholesterol and total cholesterol levels. However, one animal study in mice showed a significant increase in plasma cholesterol with the loss of housekeeping selenoprotein expression [31]. In human, selenium supplementation was found to increase total cholesterol and triglyceride levels in French adults [27]. Total cholesterol and LDL cholesterol levels also increased after selenium supplementation in the Chinese population [32]. Another study showed no further decrease in triglyceride or LDL cholesterol concentration but a blunted increment of HDL with selenium supplementation in participants with coronary heart disease receiving simvastatin-niacin treatment [33]. Therefore, the role of selenium supplementation on lipid metabolism in humans deserves further research. Recently, the apoE δ4 gene was found to play a central role between selenium levels and lipid metabolism in rural elderly Chinese [34]. The underlying interactive mechanism between susceptible gene, selenium, and lipids needs further investigation."

It seems the rodent is not such a good model for the interactions we are interested in here, not suprisingly as their lipoprotein regulation diverges from that of humans in many ways.


Thanks for having followed this investigation to its startling conclusion. Here's a reward: "12,000 Miles", from the beautiful album The Overflow by Humphreys and Keen. If you like this, you can download the entire 13-song album here for only $5US