Fish Oil, Krill Oil, and Hepatitis C

Few things in paleo-land are as endlessly debatable as whether supplementing fish oil or cod liver oil is a good idea. When considering the effects of omega-3 VLCFA (very long chain fatty acids, which describes EPA and DHA to a tee, though so does HUFA, highly unsaturated fatty acids) on HCV replication and liver health, things get even more complicated.

There's an action of VLCFA on blood lipids which isn't what we want; an increased demand for cholesterol which sees an increase in LDL-receptors (low LDL is the serum marker for this). If you've read the earlier entries in this blog you'll know that this favours fresh HCV infection of hepatocytes. And fish oil is the most inflammatory oil in models of liver disease exacerbated by excess polyunsaturates.

However, these effects can be minimised by consuming VLCFA in the context of a diet rich in saturated fat and cholesterol. A traditional fish-and-coconut, or herring and mutton,  based diet, with eggs or offal, for example. And no-one is ever going to supplement the amounts of fish oil (35% of calories) used in the alcohol/drug models of liver disease. 1% of calories as EPA and DHA - an effective dose from supplements - is about 6g fish oil or 10mls cod liver oil, about 3% and 5% fish oil calories on your imaginary 2000 kCal diet. Hmmn.

Anyhow, the fish oil-type omega 3s (which you will also find in pastured meat - lamb, goat, venison), and the omega 6 VLCFA arachidonic acid (ditto), are good and necessary things to have in the diet. 

For one thing, they all inhibit HCV replication.

This paper finds EPA and DHA effective: http://theses.gla.ac.uk/133/01/2008hubbphd.pdf

This adds AA to the picture: http://researcher.nsc.gov.tw/public/Harrison5782/Data/911201324971.pdf

 "In this study, we found that several polyunsaturated fatty acids (PUFAs) including arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) are able to exert anti-HCV activities using an HCV subgenomic RNA replicon system. The EC50 (50% effective concentration to inhibit HCV replication) of AA was 4 lM that falls in the range of physiologically relevant concentration. At 100 lM, a-linolenic acid, c-linolenic, and linoleic acid only reduced HCV RNA levels slightly and saturated fatty acids including oleic acid, myristic acid, palmitic acid, and stearic acid had no inhibitory activities toward HCV replication. When AA was combined with IFN-a, strong synergistic anti-HCV effect was observed as revealed by an isobologram analysis."

Some points: these VLCFA seem to be effective at normal physiological (non-toxic) concentrations; their vegetable precursors (LA, GLA and ALA) are not significantly effective, and neither is oleic acid (the omega 9 monounsaturated fatty acid found in meat fat and olive oil - interestingly it was called a saturated fatty acid here: compared to DHA, it is).

One way to optimize levels of DHA, AA, and EPA while minimizing the unwanted effects of PUFA on liver inflammation is to lower intakes of vegetable PUFA (cut out oils and grain, limit nuts and seeds) while eating adequate amounts of oily fish, eggs, meat and organ meats, in a context of saturated fats from coconut, dairy and animal drippings (or palm, cocoa butter).
"As the dietary saturated fat content increased, liver pathology scores and ALT values decreased (P < 0.05). At 30% dietary saturated fat, ethanol-induced hepatic necrosis was eliminated, and micro- and macrovesicular steatosis and inflammation were markedly reduced, even though the carbohydrate and total fat content of the diets and the ethanol dose were identical to those administered to rats fed the low-carbohydrate, unsaturated fat diets."
http://jn.nutrition.org/content/134/4/904.long

Should we ever supplement fish oils? There is another warning here: The administration of high amounts of n-3 polyunsaturated fatty acids reduces host defense to bacteria, viruses, parasites, or fungi. Inappropriate administration of n-3 polyunsaturated fatty acids in patients at risk of sepsis may cause adverse effects due to an increase in the susceptibility to infection. http://rd.springer.com/chapter/10.1007/978-1-60761-061-8_8

(click on "look inside" link).

Some of the benefit of fish oil might come from this very immunosuppressive action, but obviously we want to stay in the sweet spot between inflammation and infection.

Eat fish when you can; it needn't always be oily fish as the muscle of white fish such as cod is high in DHA.

Don't worry too much about mercury; anyone with Hep C should be getting a higher intake of selenium (seriously, the most important supplement you can take), which protects against mercury toxicity: http://www.ncbi.nlm.nih.gov/pubmed/23033886

Sardines are a good oily fish from low in the food chain. Canned tuna is of little use. Always buy canned fish packed in spring water, olive oil or oil-free tomato sauce; packing fish in soy oil (or "natural oil" on one deceptive mackerel label) counteracts any benefit of omega 3.

Cod liver oil has the benefit of supplying arachidonic acid, retinol and vitamin D not found in other fish oils. 

It should not be taken long-term in higher doses; a 5ml teaspoonful a day (supplying 500mg EPA and 500mg DHA) is probably safe. Concentrated fish oil pills, with more omega 3s, so you need only one or two daily, may be a good bet. But the best option for supplementation, if such is desired, is krill oil.

Krill oil is effective at significantly lower doses than fish oil because the VLCFA are in phospholipid form, not the usual triglycerides, so they get straight into the cell membranes without being oxidized (a similar mechanism might explain why whole nuts and seeds seem to be anti-inflammatory, yet their purified oils are full of pro-inflammatory linoleic acid). Krill oil, but not fish oil, reverses the elevated gluconeogenesis of diabetes, which can be a consequence of HCV infection: http://www.frontiersin.org/Nutrigenomics/10.3389/fgene.2011.00045/full

"We found that ω-3 PUFA supplements derived from a phospholipid krill fraction (KO) downregulated the activity of pathways involved in hepatic glucose production as well as lipid and cholesterol synthesis. The data also suggested that KO-supplementation increases the activity of the mitochondrial respiratory chain. Surprisingly, an equimolar dose of EPA and DHA derived from FO modulated fewer pathways than a KO-supplemented diet and did not modulate key metabolic pathways regulated by KO, including glucose metabolism, lipid metabolism and the mitochondrial respiratory chain. Moreover, FO upregulated the cholesterol synthesis pathway, which was the opposite effect of krill-supplementation."
This is pretty interesting too: http://www.ncbi.nlm.nih.gov/pubmed/21749725
Anandamide can be elevated from long-term consumption of high-omega 6, low omega 3 diets; it's a cannabinoid and and can produce - the sugar-craving munchies, just like the real thing!
(There's a cool discussion of the research by Emily Deans here: http://evolutionarypsychiatry.blogspot.co.nz/2012/09/omega-6-obesity-and-endocannabinoids.html

Anyhoo; what to recommend?

Remember to eat your saturates (see figure 1) http://atvb.ahajournals.org/content/12/8/911.full.pdf 

Eat fish regularly, but cook it in butter or dripping, or serve it with coconut...

Krill oil is the best daily omega 3 supplement, Cod Liver Oil or concentrated fish oil capsules are the best fish oils for temporary use, but are easily overdone. Limit your omega 6 intake from vegetable oils to the sparing use of olive oil, nuts, and seeds, and get some omega 3 intake from cold-weather greens (spinach, silver beet, kale, watercress). Ground flaxseed is a good occasional food for the gut. But vegetable omega-3s are no substitute for animal ones, and flaxseed oil is not worth supplementing.

The standard Paleo recommendation from the most reliable sources (Paul Jaminet, Kurt Harris) is to limit PUFA to 4% of calories. If you eat about 2/3 of your energy as fat, that fat should be about 6% PUFA on average. If half your fat comes from dripping, dairy and coconut, the other half from red and white meat, olive oil, fish,  nuts, seeds and greens, you'll come close enough to this magic figure; but it does kind of rule out taking 10mls of cod liver oil every day of your life.

I figure that we can count PUFAs in whole foods - fish and nuts - as being at least twice as beneficial and half as harmful as their purified triglyceride oils. No exact figures (except for krill oil), but good evidence that this type of difference is real. Peanuts? a) not a nut, b) source of the liver carcinogenic aflatoxins, and worth avoiding. Almonds and brazil nuts, black sesame and ground flaxseed are good sources of minerals, vitamins and prebiotics and worth having in the diet now and then.

My Dietary Recommendations for Liver Health

These are the notes I hand out at my inpatient liver presentations.
They do not promote carbohydrate restriction because they are aimed at people with alcohol and drug issues who more often than not need to eat more of (almost) everything. Nor do they include supplements, as supplementation is decided on a case-by-case issue for inpatients.
Apart from that, it includes everything I had learned about a year ago...

EATING for a HEALTHY LIVER: with regard to RECOVERY from ALCOHOL AND OTHER DRUG ABUSE and HEPATITIS C

The type of diet, and the specific foods you eat, can play a large

role in recovery from liver damage. A few substances found in common

foods can promote liver fibrosis; many specific foods have been shown,

or are suspected, to prevent it.

In general terms

1) Protein is very protective of the liver,

2) Complex carbohydrate (starch) is protective but simple (sweet)

sugars can be harmful, and

3) Saturated fat is protective, while polyunsaturated fat can be harmful.

There are 3 specific substances to minimize or avoid:

Minimize:

Fructose (found in sugar, corn syrup, fruit juice concentrate, agave

juice, honey, as well as sweet fruit).

Fructose is directly converted to fat in the liver and reduces the

insulin response to glucose; high consumption of fructose can cause

fatty liver, type 2 diabetes, gout and irritable bowel syndrome.

Whole fruit and dark honey, in limited amounts, are safe sources of

fructose for most people.

(In the Hepatitis C Virus (HCV) life cycle, fructose induces DGAT1 and

promotes VLDL expression, increasing the release of virus to the

bloodstream).

Minimize:

Polyunsaturated fats; PUFAs (from vegetable oils and non-dairy

spreads). These fats are essential only in such amounts as one might

easily obtain from a diet containing meat, dairy, eggs, and fish, with

occasional nuts and seeds. Vegetable oils contain large quantities of

omega-6 lineolic acid, which promotes inflammation and suppresses

omega-3 fats.

The popularity of omega-3 fish oil in modern times is due to the

excessive amount of omega-6 in food oils and processed foods.

When large amounts of polyunsaturated fats are added to alcohol or

drugs, liver damage and fibrosis are increased.

Persons with Hepatitis C show increased fibrosis and worse responses

to treatment with higher PUFA content of the diet.

Vegetable oils decrease LDL and HDL cholesterol, while saturated

animal fats increase both. In persons with Hep C, higher LDL and total

cholesterol is associated with a lower degree of fibrosis and a better

response to treatment.

(In the HCV life cycle, low LDL causes an increase in LDL-receptors,

which are used by the virus to infect new cells).

The fat from pork and poultry is relatively high in omega-6 PUFA, and

is not protective, whereas fat from beef, lamb, goat, venison, dairy,

cocoa, and coconut is protective.

Minimize, and if possible Avoid:

Gluten grains.

Wheat (flour, bread, pastry etc.), Rye, Barley, Spelt, Kamut, Oats.

These grains contain glutenin and gliadin (proteins), together with

agglutinating lectins, phytates, and fructose-containing fibre (FOS),

which can damage the gut when consumed in the excessive amounts found

in the modern diet (it’s not just the gluten that’s harmful in these

foods). Whole grains contain more agglutinin lectins, phytates, and

FOS than white flour, which is however lacking in most vitamins and

contains added iron.

Gluten grains cause “leaky gut” (increased intestinal permeability)

which allows bacteria and toxic undigested proteins to enter the

bloodstream from the gut.

Parts of these bacteria called LPS can trigger inflammation in the

Liver.

Persons with Hepatitis C have an increased rate of Coeliac disease, a

gluten sensitivity disease. Coeliac and non-celiac gluten sensitivity

can cause liver cirrhosis, gall bladder disease, and diabetes (types 1

and 2), as well as most of the autoimmune diseases common in people

with Hepatitis C.

Humans have been eating grains for a relatively short period of our

history and have not had time to adapt properly to a food that poses

so many digestive challenges.

Grains supply no nutrients not found in other foods; meat, eggs,

dairy, nuts and seeds are better sources of protein, vitamins and

essential fats, while root vegetables and tubers are better sources of

starches, and green vegetables are richer in protective

phytochemicals. White rice, quinoa, buckwheat, millet are non-gluten

grains that are tolerated by most people. Some people who do not

tolerate other gluten grains can tolerate oats in small amounts.

Some special foods that protect the liver:

Beef consumption is related to lower rates of cirrhosis, and this is

probably true for all red meats. The same is true for eggs. However

pork and processed meats (which are mainly pork) may increase

cirrhosis. Red meats are best.

Spices, including turmeric, fenugreek, saffron, garlic, vanilla are

protective against fibrosis.

Coffee consumption protects against fibrosis and cirrhosis from

alcohol and possibly Hepatitis C. Green tea (and possibly black tea)

protects against fibrosis, but this effect may be reduced by milk in

tea.

DHA from oily fish is protective against fibrosis in moderate

supplement doses but may increase it in excessive amounts.

Lecithin, betaine and choline protect against fatty liver; these are

found in eggs, chocolate, liver and kidney, and fish roe (lecithin and

choline), and in beetroot and spinach (betaine).

Beetroot contains betaine and some unusual and potent antioxidants,

betalains, which are destroyed by cooking (boil beetroot for less than

15 minutes, roast for under 1 hour).

Vitamins A and K2 protect against liver cancer and are found in animal

fat, organ meats, fermented dairy foods, and (K2 only) spirulina and

fermented soy.

Brazil nuts are the richest source of selenium, which also protects

against liver cancer and fibrosis. Each nut contains 19mcg selenium; 4

a day is enough. Meat and seafood are also good sources of selenium.

Carotenoids, folic acid, and flavonoids protect against fibrosis and

are found in green leafy vegetables; sulfur compounds found in

cruciferous veges (cabbage, broccoli, mustard, radish etc.) stimulate

immunity and protect against cancers.

OPCS, astringent polyphenols found in grape seed, pine bark, cocoa,

berries, and apples, protect the circulation of the liver, and protect

against the blood cancers (lymphoma) associated with both Hepatitis C

and coeliac disease.

Chinese mushrooms such as shiitake, black and white fungus, etc.

(dried or fresh) have benefits for the liver and immune system.

Eat FOOD: don’t eat food products. If possible cook it yourself or eat it raw.

These canned foods are good: sardines, tuna, mackerel: tomatoes,

beans, beetroot: olives; and bottled (not canned) pasta sauces. Frozen

vegetables and berries are excellent foods. Prunes and raisins are

good dried fruits.

MTR boil-in-a-bag curries are good occasional convenience foods.

Try to avoid processed meats, pure beef or venison sausages are the

best varieties.

It is not necessary to try to eat all the special foods. These are

good if you have them and like them, but you will not die from their

lack.

Eat some red meat, eggs, and occasional fish; some dairy (especially

butter, cream, yoghurt, or aged cheese) if this suits you; some

starchy vegetables (potato, kumara, carrot, swede, yam, beetroot,

peas, etc.); some green vegetables - raw or cooked (spinach, cabbage,

cauliflower, celery, lettuce, etc,); and some fruit or berries. Use

spices, onion, garlic, extra virgin olive oil, or herbs for

flavouring. Eat fresh nuts and seeds in moderation if you like. Enjoy

dark chocolate, coffee, tea, herb tea, fruit tea, as far as possible

unsweetened (cream can be a good substitute for sugar in coffee and

cocoa). Drink clean water regularly. Do not overdose on “fibre”.

Cook food at lower temperatures (below 200C in the oven; 170C is good

for roasting most things), remember water in a dish (as with soups and

casseroles) helps to control temperature, and fry and roast with

traditional fats, especially beef and lamb dripping, or butter and

ghee. If a meal needs oil use extra-virgin olive oil. Pan-roast chips

rather than deep-frying.

Some references:

Dietary Fat and Alcoholic Liver Disease; a concise review. Esteban Mezey

Alcohol and dietary intake in the development of chronic pancreatitis

and liver disease in alcoholism.  E Mezey, et al.

Fructose, PUFA and Gluten papers linked to Hyperlipid blog (use blog

search function)

Gluten Grains, Carbohydrates and Fats sections of Archevore blog (ditto)

Beef fat Prevents Alcoholic Liver Disease in the Rat; Nanji et al.

Relationship between Dietary Beef, Fat, and Pork and Alcoholic

Cirrhosis; Bridges

Dangerous Grains; book by Hogan and Braley.

Life Extension Foundation website: Health Concern: Hepatitis C (for

advice on supplements and drugs)

Applying principles of HCV virology to the Development of new

Antiviral Therapies; Stephen J. Polyak

(c) George D Henderson 2012


Feel free to use this.

A video of my 2009 working holiday in New Zealand's scenic Southern Alps. Music: Walrus Arabia, by The Puddle. I'm the one with the moustache and the guitar, Gavin wears the hat and the bass, and my brother Ian was behind the camera, the drumkit, and the steering wheel.

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.
http://www.salk.edu/news/pressrelease_details.php?press_id=560
http://www.cell.com/cell-metabolism/abstract/S1550-4131(12)00189-1

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.

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. http://www.spiked-online.com/articles/0000000CAE78.htm 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.  http://www.archevore.com/get-started/ by Dr Kurt Harris, and http://perfecthealthdiet.com/the-diet/ 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." http://onlinelibrary.wiley.com/doi/10.1002/hep.510260112/pdf referenced in "Dietary Fats and Alcoholic Liver Disease" by Esteban Mezey: http://onlinelibrary.wiley.com/doi/10.1002/hep.510280401/pdf

Vitamin D3 could save your life, pretty much.

http://hepatitiscresearchandnewsupdates.blogspot.co.nz/2012/09/d-livering-message-importance-of.html#.UFoZ4bJlTzw

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. http://www.sciencedirect.com/science/article/pii/S0891584900002963
Vitamin K2: http://www.ncbi.nlm.nih.gov/pubmed/17541221

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.
http://www.ncbi.nlm.nih.gov/pubmed/18978503 

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:

http://www.meandmydiabetes.com/2012/08/11/western-states-100-low-carber-wins-ultramarathon-steve-phinney-and-jeff-volek-study/

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?

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.

http://www.ncbi.nlm.nih.gov/pubmed/16447275

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).

Neurotransmitters

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 http://www.ncbi.nlm.nih.gov/pubmed/16165703- 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

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 http://www.ncbi.nlm.nih.gov/pubmed/21816960
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

5    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

6    Yin SS, Wang BE, Wang TL. The effect of Cpd 861 on chronic hepatitis B related fibrosis and early cirrhosis: A
      randomized, double blind, placebo controlled clinical trial. Zhonghua Ganzangbing Zazhi 2004; 12: 467-470

7    Wang TL, Wang BE, Zhang HH, Liu X, Duan ZP, Zhang J, Ma H, Li XM, Li NZ. Pathological study of the therapeutic effect
      on HBV -related liver fibrosis with herbal compound 861. Weichangbingxue He Ganbingxue Zazhi 1998; 7: 148-153