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.

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.

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.

Ever since I was a teenager I've been a hay fever sufferer. For months at a time my nose is irritated by pollen, perfume, cheese, and bright sunlight, my eyes made gritty by cobwebs and house dust. I sneeze not once or twice but unstoppably. This syndrome may seem trivial, but it can be endlessly distracting and exhausting. When I was young I took antihistamines such as Actifed, but this just made me feel worse in a different way (my skin crawled instead of my nose).
Antihistamine use correlates with elevated suicide risk; this doesn't surprise me. http://www.ncbi.nlm.nih.gov/pubmed/22075102
More recently I've found I can get some relief by smoking cannabis to dry out my nose and mouth, but of course this is a drug that has other effects that might not always be appropriate to one's lifestyle.
During the years I was heavily addicted to opioids my hay fever was in remission. Opioids tend to deplete histamine by releasing it indiscriminately, often causing itching as a consequence, but never hay fever. Sadly, I had to throw out this particular baby with all that dirty bathwater.

A few years back I had an enlightening experience. My family was staying over summer with the whanau at a camping ground on their marae (look it up). This kind of communal living close to nature and other people is deeply rewarding on all sorts of levels, but the facilities are of necessity undeveloped, there are little kids with dirty hands everywhere and no clean running water (we drank bottled water). We left with a case of mild diarrhea, and I stopped at the nearest town to get some probiotics; my partner and I also suffering badly from hay fever. I bought L. rhamnosus plus L. reuterii for some reason. Which quickly stopped the GI symptoms but also remarkably put a stop to our hayfever. A pretty amazing effect that lasted for some time afterwards.

But later on, the probiotics weren't a reliable cure; sometimes they even seemed to make it worse. High doses of grape seed extract (200mg OPC before meals) attenuated the cheese reaction (maybe because grape polyphenols bind to casien; this effect is used in wine fining), but there was little, maybe nothing I could reliably do when the fever was really bad (except smoke dope, which I am increasingly reluctant to do).

A few weeks ago now I read "An Epidemic of Absence" by Moises Velasquez-Manoff
"Allergic and autoimmune conditions are far more frequent in rich countries than poor ones, even among genetically identical populations (West Germany far outpaced East Germany in their frequency, as does Finland compared with an impoverished adjacent territory under Russian control). Societies where intestinal parasites are the rule seem to lack them completely."

Now, I don't have access to whipworms and hookworms, but maybe there is something I can do to test this hypothesis?
What if - all good hypotheses must start "what if" - what if the favourable effect my partner and I obtained from probiotics that past summer was in fact also due to the bacteria causing the gastro-intestinal upset? What if bacteria not usually part of our gut flora, plus probiotics, supplied what I might call a broad-spectrum immune tolerance effect? For geeks of this stuff (and I know more about it now than I'm going to let on here - looking into immunology will quickly take you down the rabbit hole and through the looking-glass and should not be indulged in lightly), I mean supplying a variety of PAMPs with activity across a wide enough range of TLRs to mimic an everyday ancestral exposure.

How to replicate this? Eating dirt? Swallowing my goat's droppings? (Bear Grylls considers deer droppings a desirable supplement.) These options suggested themselves, but did not recommend themselves.
Fortunately I have a well in my backyard; it's fed by mountain rainfall, seeps down through the soil and rock and up through mud, weeds and algae. I know it's full of saprophytic bacteria (feeding on decayed plant matter) because if I let it stand it soon becomes brackish. I drink it often with no ill-effects, but I've never drunk it constantly or looked for a correlation with my hay fever symptoms.

Experiment - to drink the well water often enough (at least 3 times a day) that the pseudocommensals (non-probiotic, non-pathogenic bacteria, algae, etc. consumed with food and water) it contains are always in my gut; to avoid treated water or bottled water and see what happens. To also notice if taking or not taking probiotics makes any difference.

Results: Hay fever has not returned (it is November in the Southern Hemisphere and my partner, who's not drinking the water, is complaining of, I mean reporting, symptoms). I sneeze every few days but only once at a time; the double sneeze has only happened once, and there is never long-lasting irritation. Most convincingly, I can clean cobwebs with absolutely no eye irritation. My cobweb allergy is not seasonal in any way, so this is unlikely to be co-incidence. And it wasn't actually part of the original hypothesis as I never considered it to be hay fever.
Not only do I react to cheese less, I crave cheese less, and eat less of it, which is an interesting observation for this long-time fan of Richard Mackarness. http://www.independent.co.uk/news/obituaries/obituary-dr-richard-mackarness-1303347.html

I would rate my symptoms now, as a percentage of what they usually are at this time:
sensitivity to pollen and perfume: 10%
sensitivity to sunlight:                    0%
duration of irritation:                      5%
sensitivity to cobwebs:                  0%
sensitivity to cheese: 30%

Probiotics don't seem to be required for these benefits.
I am on tour at the moment and away from my well, without access to safe "raw water". We'll see if any symptoms return in the few days I'm away.
It's also possible I'm a bit happier and more contented, less irritable and distracted, now. It's hard to be sure as life is a journey and you can never drink the same water twice. We'll see.

This was an n=1 experiment and placebo effects are no doubt considered possible. But I have to admit to being something of a placebo skeptic. When you're a drug addict people are always trying to give you placebos and you soon lose any ability to be fooled by your expectations.
Placebos in RCTs seem to be more about controlling for the circumstances of the test (white coat syndrome) by making them as identical as possible, than about any magical effect of mind over matter.

My partner hasn't yet drunk from the well, nor will my children go near it. This seemed crazy to me, avoiding a healthful water source that our ancestors would have been lucky to have. But it also makes sense; the instinct to always prefer the very cleanest water, and distrust everything else, has made sense in evolutionary terms - until very recently.

Video: Dr Richard Mackarness - father of Paleo, from 1958

Back to the raison d'etre for this blog; the supposition that HCV replication can be restricted, and the symptoms mitigated, by following a carbohydrate-restricted, low-PUFA, high SFA diet.

Another way of looking at this is, genomically. HCV promotes certain genes that it finds helpful, and manipulates others;

HCV promotes -
FOX01 - this transcription factor increases the production of glucose, which, amongst other things, inhibits PPAR-alpha, a gene that is unfriendly to HCV. FOX01 is also activated by fructose.
DAGT1 - this protein synthesizes triglycerides from dietary fats and carbohydrates. It is also stimulated by glucose and fructose - dietary carbohydrate. The tryglcerides are released as VLDL, which the HCV virion accompanies.
HMG-CoA reductase. This protein synthesizes a geranylgeranyl group which HCV needs to activate another gene. The end product should be cholesterol, but HCV disrupts cholesterol completion in order to keep the protein working. Dietary cholesterol inhibits HMG-CoA reductase.
LDL-cholesterol receptor complex (LDL-R) - an array of proteins that HCV virion uses to infect liver cells. HCV promotes LDL-R indirectly by restricting hepatic cholesterol production. A diet high in PUFA (seed oils) promotes LDL-R, a diet high in saturated fat reduces LDL-R expression.

PPAR-alpha: this gene inhibits DAGT1 and HCV replication. This is the basis for the HCV inhibiting effect of the grapefruit flavanone naringenin. PPAR-alpha is activated by fasting, calorie restriction, and carbohydrate restriction, as well as the omega-3 fatty acid DHA and naringenin. It is the fat-burning gene, pretty much; it inhibits the conversion of free fatty acids (fuel form) to triglycerides (storage form).

The presence of an active HCV infection can be metabolically disruptive, leading to type 2 diabetes and fatty liver. This review shows the link between low cholesterol and diabetes:
http://beforeitsnews.com/healthcare/2012/11/hepatitis-c-virus-infection-and-diabetes-not-a-straightforward-relationship-2443048.html

In a meta-analysis of 34 studies, HCV infection was found to increase the risk of diabetes in both retrospective (adjusted odds ratio 1.68, 95% CI 1.15–2.20) and prospective studies (adjusted hazard ratio 1.67, 95% CI 1.28–2.06).[1] Furthermore, patients with HCV infection have higher risk of diabetes than patients with hepatitis B virus (HBV) infection.
By multivariate analysis, HCV infection was independently associated with diabetes only in subjects without hyperlipidemia (defined as triglycerides above 150 mg/dL and/or total cholesterol above 200 mg/dL; adjusted odds ratio 1.35, 95% CI 1.17–1.55) but not in those with hyperlipidemia.

Interestingly, high triglycerides were inversely associated with diabetes (but note that this was either/or - it was not necessary to have both cholesterol over 200 and TG over 150 for protection). This can be explained in a number of ways; high TG is a sign of insulin sensitivity on the usual high-carbohydrate diet; it shows that the liver is responding to the diet naturally; that blood sugar is being kept low by lipid synthesis.
This is matched by the surprising finding that low HDL is associated with SVR (sustained viral clearance after antiviral treatment). http://www.ncbi.nlm.nih.gov/pubmed/20568303

In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001).

If low HDL is the usual response to the usual diet, it may be just a sign of liver function and low viral titres.
I suggest that higher TG and lower HDL are not important signs unless you choose to eat a diet that should promote these anyway; in which case they are signs of normality, if not of health.

Serum TG may be lowered by HCV because cholesterol production is low; in this case, the TGs will have trouble being packaged and exported, and fatty liver will result (similar to what happens when choline, also required for triglyceride export, is restricted).
Despite HCV depending on TG and VLDL cholesterol, this benefits the virus, because low levels of lipids and cholesterol see a bigger effort from cells to take in the amounts present (more LDL-R). With fewer lipid particles in the blood, and more LDL-R, the LDL-R are more available to bind to the HCV virions.
(Technically, this refers to some parts of the LDL-receptor complex like the friendly-sounding protein Niemann-Pick C1 like 1:
http://www.ncbi.nlm.nih.gov/pubmed/22231557 )

Can HCV, justly famous for its high rate of mutation, often one step ahead of your antibodies, mutate to use different receptors? Certainly, with regard to the LDL-R complex proteins required there seem to be variations among the samples studied. It is possible that HCV quasispecies could arise that can leave infected cells without VLDL exocytosis and enter without the LDL-R. But highly variant quasispecies are not very viable. Lipid transport is the "main road" that HCV exploits. There is a lot of traffic down that way. Taking another route would see the virus marginalized and struggling to survive.
Consider the metaphor of the tank.

Tanks are all-terrain vehicles - they can travel where cars and trucks cannot. Yet most tank campaigns in history have been battles for control of the roads and railways, which allow faster deployment of larger numbers of tanks.

The lipid transport system is to HCV what this railway is to the tanks. Higher cholesterol and LDL counts represent more empty trains. Lower counts represent empty stations with lots of helpers ready to unload the trains, trains that are more likely to be carrying tanks.

The ideal cholesterol level is over 200, but probably not that much over (220-240 seems to be about right). Lipids, like blood glucose, are a form of energy and therefore a response to how much we eat as well as the type of foods we eat; it may also be that the people with the high-TG, low-HDL, high cholesterol picture were eating more and therefore tended to have better immunity than other patients who were off their food, perhaps due to poverty, food allergies, or anorexia. You can alter lipid counts by eating more or less food, as well as by changing the kinds of food you eat.

While I think ketogenic dieting - for short periods - or intermittent fasting, which should generate intermittent ketosis - is a powerful tool against HCV, there is one dissenting voice:
Paul Jaminet has written "Ketogenic diets, which starve the brain of glucose but feed it with small molecules derived from fats, are highly effective against bacterial infections of the central nervous system, since bacteria depend on glucose metabolism. But hepatitis B and C viruses can utilize the process of gluconeogenesis—manufacture of glucose from protein—for their own benefit, so people with hepatitis benefit from higher carb diets."
http://www.psychologytoday.com/blog/perfect-health-diet/201201/is-there-perfect-diet
Firstly, by higher carb Paul doesn't necessarily mean food-pyramid high. About 50-75g carb per day is enough to suppress ketosis and gluconeogenesis (this is about the amount I usually eat). He is probably right that this will result in lower blood glucose and more metabolic flexibility in some people with HCV than following a ketogenic diet. Paul also recommends restriction of fructose and PUFA, and intermittent fasting, in general terms (the line about gluconeogenesis seems to be his only specific HCV reference).
However, the FOX01 activation, though important to HCV, is only part of its arsenal. We also need to consider the DAGT1, which will be highly suppressed on a ketogenic diet (which is where PPAR-alpha becomes most active). And, paradoxically, FOX01 can be suppressed by deep ketosis (presumably when ketone bodies are produced in amounts that begin to reduce the brain's requirement for glucose).
The compromise that I find comfortable is to eat a little "safe starch" carbohydrate once a day, plus a piece of fruit, and fast intermittently (as described in "Dining in the Fourth Dimension"). My viral load was lowest in ketosis, but it is not much higher now and I am even more comfortable.

Butter at War

This is my new favourite blog: http://nelliebswartimerationing.blogspot.co.nz/2012/11/butter-rationing-in-new-zealand.html

A family living on New Zealand wartime rations.
Some silly people say that wartime rationing produced healthier people, not because cigarettes, alcohol, and sweets were harder to get, but because less saturated fat was being eaten.
Let's see, shall we?

The following information was issued by the Department of Health, Wellington, New Zealand, in 1943.

Butter Rationing

Compensating Foods Suggested.

With the introduction of butter rationing, it is important that people should know the foods that can help to compensate for the loss of food value normally supplied by the quantities of butter to which they have become accustomed.

In the first place, butter is butterfat, and the two other foods which contain butterfat are milk and cheese.
The amount of milk normally required daily is :

Two glasses for Adults

Three to Four glasses for Children.

With less butter available it is necessary that all of this milk - and more, if possible - should be used.
The top creamy milk should be saved for the children's porridge and puddings.

More cheese should be used.
Grate it in salads, eat it in chunks with bread and a little of your butter, or cook it for the evening meal.

An important constituent of butter is Vitamin A, which enables the body to resist infection, and also helps to avoid the condition known as night-blindness.
Vitamin A is present, for example, in eggs and liver.
Cheese, eggs, and liver are all foods which can form part of the tea meal - the meal at which so much butter was eaten.

The green and yellow vegetables - leafy vegetables, carrots, kumeras (NZ sweet potato) - can all help in providing Vitamin A. So can tomatoes.

To replace the Vitamin A, then, use milk, cheese, eggs, liver, green and yellow vegetables and tomatoes.

For baking purposes dripping clarified at home may be used, and if the butter for spreading runs out, salted beef dripping in which an onion has been cooked, is suggested as a substitute.

To sum up, the following foods will help to make up the deficiency caused by butter restrictions :

1. milk and cheese

2. eggs and liver

3. green and yellow vegetables and tomatoes

4. salted beef dripping for spreading on bread

5. clarified dripping for baking.

- My God, governments knew more about nutrition then than they do now!

As in this Disney WW2 nutrition film:

The opening up of the slippery downward slopes in New Zealand governmental nutritional policy dates from 1974:

"Margarine could not be sold to the public from 1908 until 1974. To get it before 1974, you needed a doctor's prescription. When the ban was ended, the dairy industry asked for another concession -- that Margarine manufacturers be forced to colour it blue. This time, Parliament told them to get stuffed. The gravy train for them had ended."

I was saddened to learn of the death of independent researcher Rich Van Konynenburg PhD. last month.

Rich was a researcher into the causes and treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) and his outstanding contribution was to grasp the importance of glutathione and the methylation cycle to this disease, then adapt the autism research of Dr Amy Yasko to suggest the concept of methylation cycle blocks and deficient antioxidant protection from glutathione as its characteristics.

There is a vicious cycle mechanism; glutathione protects B12 from the denaturing effects of, for example, mercury or peroxynitrite, and B12 is the co-enzyme that transfers methyl groups to homocysteine, creating SAMe (AdoMet).

This hypothesis struck me as obviously relevant to hepatitis C. Liver disease is produced experimentally by dietary deficiencies, i.e. a diet deficient in choline (a methyl donor) and/or methionine (the source of both SAMe, a methyl donor, and the cysteine moiety of glutathione). Deficiency of selenium will cause hepatic necrosis, and selenium is the co-factor for those enzymes that use glutathione to remove free radicals.

I contacted Rich Van Konynenburg by email and corresponded with him for some time. Re-reading my emails they are breathless and prolix, and there were too many of them, and Rich's replies are detailed and not at all dismissive. He corrects my mistakes gently and encourages my interest.

Rich was like the hedgehog in Isaiah Berlin's parable who knew one thing but knew it very well. He knew the methylation cycle and transsulfuration pathways (the parts of biochemistry concerned with the non-protein functions and metabolism of the essential amino acid methonine) intimately, the proteins and genes involved, the polymorphisms that influenced metabolism one way or another, and how this related to various diseases, especially CFS/ME, autism, and Lyme disease.
The methylation cycle and transsulfuration pathways are a good place to start if you are interested in biochemistry, because their simplicity belies their overall importance to health. There are only 3 vitamins required (folate, B12 and B6) and 3 minerals (magnesium, molybdenum, and selenium), yet the products of the system include many of the chemicals popular as energy supplements; carnitine, creatine, phospholipids, taurine; and of the neurotransmitters, besides the role of glutathione and taurine in bile production and of both methylation and glutathione in neutralizing toxins.

This site gives a link to Rich's many papers; and here is the wiki page on which the hypothesis was expounded and referenced in all its detail. Anyone familiar with the work of Chris Masterjohn at Weston A. Price will know about the importance of glutathione and choline in the diet - here is the repository of the technical and clinical data that underlines that importance.

Both Rich's help, and the example provided by his very existence as a respected independent health researcher, were of the utmost encouragement to me as I strove to educate myself. His scrupulous accuracy and honesty - exemplified by his case reports of adverse reactions to his suggested treatment protocol - set a high standard for others to aspire to. My regret is not being able to catch up with him again before his sudden death.

The other day a new dog owner asked for my advice about what to feed a dog. Bluebelle has been eating mainly paleo after her first year, when she seemed to be getting health problems from a diet of dried food and mince. These included trouble pooing and stiff hips or sore legs. She no longer has any of these problems, but we did have an issue with iodine deficiency on the new diet - see below.

A mainly carnivorous animal like Bluebelle (to wit, a dog) needs to eat muscle, connective tissue (gristle and skin), bones, organ meats, and fat to be healthy, from a range of animals including some fish. It is an omnivore and can tolerate some carbohydrate from starches and fruit, but should not have grain-based dry food often (OK for emergencies but not as regular diet).

In terms of calories there needs to be 4-5 parts fat to 1 part protein. Fat is much denser than protein and all meat has some fat in it, so this mostly means using fatty meats or adding a little fat to the dish.

Kelp powder should also be added to the food occasionally to prevent iodine deficiency and hypothyroidism (we learned this the hard way), and salt added to cooked meals.
Symptoms of low iodine include “spooky” behaviour and depression, hair loss, discoloured patches on skin, and in Bluebelle’s case susceptibility to mastitis and allergies and hunched, stiff “aged” posture. This was quickly and completely reversed by kelp, which had a rejuvenating effect like watering a wilting plant. This was only diagnosed by my habit of reading the excellent Hyperlipid blog of vet Peter Dobromylskyj, who mentioned the symptoms in passing, for which I'm eternally grateful; our vet had drugs for the symptoms but didn’t recognise the cause.

Onions and garlic can be toxic to dogs (and cats, causing Heinz body anaemia) but most other veges are safe (and they will generally avoid onions anyway) when feeding leftover meat dishes. The inability to detoxify onions tells you that a dog is not as completely omnivorous as say a pig or human and its ancestors probably never survived by eating roots, shoots and leaves. Though, come to think of it, my goat wouldn't eat onions either. Gophers like them, apparently, and pigs aren't harmed by them (though some warn against feeding onions to pigs, research seems to show benefits).

We feed Blubelle:

Minced beef and lamb

Beef (ox) heart, lamb heart, cut into cubes, raw

Offal: Liver or kidney (lambs or calves or ox or chicken) COOKED (lightly fried in dripping with salt, once or twice a week). If we don’t include some salt, Bluebelle drinks more sea water, and not all dogs have access to salt water.

Note: pork hearts tend to be flabby, pork kidneys I’ve bought have been deformed, coming from caged animals, so I don’t generally buy these or commercial lard. A bit of bacon scrap accounts for most of the pork in her diet.

Bones - beef bones probably best, also chicken necks, raw.

Kelp powder - a small teaspoon mixed in or sprinkled on food every few days.

Fats - we add a couple of tablespoons dripping (beef and lamb) or if available, free-range lard, to the less fatty meals. If the dog eats dripping (tallow in the U.S.), which is fairly flavourless, then it definitely needs fat. Bacon rinds or bacon grease and offcuts of the meat you prepare for yourself are also good.

Fish - a tin or sardines or half a tin of mackerel once a week keeps the coat shiny.

Chicken - we feed Bluebelle our roast chicken leftovers, including the bones. This may not be for every dog but it hasn't done her any harm.

Cheese - Bluebelle loves cheese, and enjoys milk and cream and yoghurt every so often. When the milk's a bit off, offer it to the dog. Probably not an everyday food though.

Fruit - Bluebelle likes a few raisins or diced prunes occasionally. Other dogs like apples and pear cores, but she doesn't seem to. She won't eat potatoes or rice or cooked greens unless these are stirred into meat, so we don't offer these unless there's a very meaty leftover stew.

Dried food - Bluebelle eats toast crusts occasionally and will eat dog biscuits if there's nothing else, so it's a good emergency food occasionally, but it wasn't good for her digestion when she ate it more often. If you get a dog roll, I recommend looking out for the rice-based (gluten-free) versions, or for dog rolls higher in fat and lower in carbohydrate.

Water - Bluebelle doesn't always drink water, but when she does, she needs a lot, so always have some available.

Timing - Bluebelle is fed once a day, in the evening. If she's not interested in food, she's not fed until she asks for it; so every now and then she goes without. She's fed about a pound or more a day; if she asks for more, she'll get it. She might turn up if someone is eating cheese, in which case she'll always be given a bit, and any uneaten or old cheese (cheddar) is given to her.

Illness - it's probably worth giving a little cod liver oil in winter for vitamin D, Bluebelle loves this; just a teaspoon a day.
Parvovirus and distemper are lethal diseases of dogs which are similar to cholera in humans. The dog dies of dehydration, loss of fluids and electrolytes. Dogs can be kept alive till the disease passes (about a week) by force-feeding, twice a day, water and Gastrolyte, or other human "oral rehydration" formula (made up strictly as advised on the packet). I have saved two dogs suffering from parvovirus by this protocol; the dog that received the formula as soon as it became ill suffered no lasting effects, the other dog, which I treated after 3 days, was always a bit skinny afterwards. Another dog that was accidentally taken to the vet and received antibiotics, not rehydration (which a vet could give by IV drip), died there.
I don't know why this isn't widely known.

I'm sure this is a case where many readers will have dogs with unusual dietary needs, or have had experience of deficiencies, diseases and toxins that we can all learn from, so feel free to use the Comments facility. I think my own ideas are working well, but I don't consider them the last word yet.

There's a paper casing a big buzz in the Hep C forums, with good cause.

Valine, a Branched-Chain Amino Acid, Reduced HCV Viral Load and Led to Eradication of HCV by Interferon Therapy in a Decompensated Cirrhotic Patient

The HCV viral load plummeted, from 5 log to less than 1.2, by the twelfth week of treatment (and only then was the patient given Interferon-alpha, one of the usual antiviral drugs, not very effective at all used on its own). This required fairly high intake of l-Valine, peaking at 12g/day. Which probably isn't something you'd want to do for more than 12 weeks. Alpha-fetoprotein also dropped back to normal, which is all to the good as elevated AFP is considered a risk marker for hepatocellular cancer.

OK, so this is just one patient. An n=1 case study, so it's properly documented and peer-reviewed (not to be mistaken for any kind of an anecdote). Case studies tell us what CAN and DOES actually happen, but not how often it might be expected to happen (RCT study) or why it might happen (animal testing, usually).

How might it work? The authors suggest various mechanisms, but there is no detail as to how, for example, l-Valine might activate dendritic cells or improve liver function. I would like to suggest one. This is not a theory, it is not even a hypothesis, just something it might be rewarding to look at.

When amino acids, carbohydrates and (to a lesser extent) fats are metabolized by cells, the energy blocks (called substrates) are fed into the TCA (tricarboxylic acid), or Krebs (after its discoverer), or citric acid cycle. (at the bottom of the above diagram). This cycle generates energy (ATP and GTP), a variety of substrate building blocks for making sugars, amino acids and lipids etc, and reducing equivalents (NADH+ and FADH2) that are used to keep the cycle working and to reduce oxidised ubiquinone (co-enzyme Q10) to ubiquinol.

The TCA cycle generates NADH+ and ATP at a few points but only generates GTP (in hepatocytes) and significant amounts of FADH2 in two consecutive reactions. These are the conversion of succinyl-CoA to succinate, and the conversion of succinate to fumarate, respectively (have a look at table 13 in this paper, where FADH2 is called FPH2, to see what I mean. 484 of 562 mitochondrial FPH2 are generated at this step). Substrates can be removed from the cycle or added to it at many points, so that it rarely runs evenly. If the succinyl-CoA substrate was drastically undersupplied, for example by removal of a previous substrate or by inhibition of a previous enzyme, there would be a deficiency of FADH2 (which might lead to inhibition elsewhere in the cycle).

(The purpose of GTP in hepatocytes is something I know nothing about, but it must have a function distinct from ATP).

Now, how is extra succinyl-CoA made available to the TCA normally? (it's called an anaplerotic reaction, by the way). From the breakdown of l-Valine mostly. Some also comes from metabolism of odd-chain fatty acids and phytanic acid, which are mainly present in the diet from dairy foods and ruminant fat.

Feeding succinyl-CoA into the TCA cycle might be expected to increase the ratio of FADH2 to NADH+ in the mitochondrial respiratory complex. Peter at Hyperlipid has speculated at length on the implications of the FADH2:NADH+ ratio in his recent Protons series.

Disclosure:
There was a corroborating paper but I lost it. Something about succinate inhibiting viral replication in vitro (as did DHA, AA, and EPA in that order). Or, maybe it was suppressing excess gluconeogenesis in infected hepatocytes (another function of long-chain EFAs) - as l-Valine is a gluconeogenic animo acid this isn't as likely, but I can't rule it out. The first time I've lost a paper and, to my shame, not been able to quickly search it up again. I found it a few weeks before I read the l-Valine paper, while researching fish oil and krill oil. If anyone knows what paper I'm referring to... Anyway, there is definitely a succinate-counters-HCV connection on record out there somewhere.

So is "fixing" the TCA cycle undoing something that HCV has manipulated for its own benefit? Does HCV virion assembly require lots of alpha-oxoglutarate, depleting succinyl-CoA? Does the extra supply of succinyl-CoA mean an equal amount of another substrate has to come out of the cycle (cataplerosis), and if so, what? And does this also apply to dendritic cells? I could go on (about HCV core protein inhibiting mitochondrial respiratory complex I and FADH2 feeding complex II, for example), but I've given you enough homework for the Xmas break.

Zinc Supplementation Improves the Outcome of Chronic Hepatitis C and Liver Cirrhosis (2009)

Zinc supplementation therapy improves the outcome of patients with chronic hepatitis C (2012)

This makes sense because HCV sequesters zinc in one of its proteins, and a zinc metalloprotein is required to break down collagen (fibrosis is a repair process and the extra collagen scaffolding - scarring - is meant to be removed). You won't recover from fibrosis if you don't get enough zinc (you need more than just zinc, but these studies show that zinc alone can give significant protection). They used polaprezinc, which is a carnosine-zinc chelate supplying 33mg/day.

A recent review from New Zealand summarizes the evidence that sugar (and high-GI starches), not fat or salt, is the main dietary cause of cardiovascular disease (PDF). John Yudkin's ghost is smiling.

An update on the hygeine hypothesis n=1. I have had one day of hay fever, moderate by previous standards but there nonetheless. I modified my protocol by restricting cheese (the obvious hole in the first n=1 post) and by restoring probiotics (either lactobacillus/bifidus or Del Immune V), which hadn't prevented hay fever without "raw water" therapy, but which seem to be synergistic in combination with it. And everything has been fine since. it's high pollen weather, midsummer, everything's flowering, other people have hay fever but mine is minimal.

P.S. Just a little Christmas bonus:

Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma

We investigated the association between fish and n-3 PUFA consumption and HCC incidence (n = 398) in a population-based prospective cohort study of 90,296 Japanese subjects (aged, 45–74 y). Hazard ratios and 95% confidence intervals (CIs) for the highest vs the lowest quintile were estimated from multivariable adjusted Cox proportional hazards regression models. We also conducted subanalyses of subjects with known hepatitis B virus (HBV) or hepatitis C virus (HCV) status, and of subjects who were anti-HCV and/or hepatitis B surface antigen positive. All tests of statistical significance were 2-sided.

Results

Among all subjects, consumption of n-3 PUFA-rich fish and individual n-3 PUFAs was associated inversely with HCC, in a dose-dependent manner. Hazard ratios for the highest vs lowest quintiles were 0.64 (95% CI, 0.42–0.96) for n-3 PUFA-rich fish, 0.56 (95% CI, 0.36–0.85) for EPA, 0.64 (95% CI, 0.41–0.98) for DPA, and 0.56 (95% CI, 0.35–0.87) for DHA. These inverse associations were similar irrespective of HCV or HBV status.

Fatty liver (steatosis) is pretty much the precondition of fibrosis, cirrhosis and hepatocellular cancer.

Steatosis and hepatic IR are closely associated but it is still poorly understood whether it is steatosis which causes IR, or vice versa. It is clear however that steatosis and IR usually precede inflammation, fibrosis, and cirrhosis of the liver.

Steatosis is produced experimentally in animals by a) toxins and alcohol – in which case the effect will be made worse by high-PUFA diets, reversed by diets providing highly saturated fats, usually beef tallow or coconut oil, and kept stable by moderately saturated fats such as olive oil and lard, b) high-fat diets (high PUFA) with round-the-clock feeding (but not with feeding in a time-restricted window), c) diets deficient in choline, or in the raw materials needed to make choline; methionine, folate and B12 (however, deficiencies of B12 and folate have other serious effects which might mask their importance in this regard), d) diets deficient in antioxidants that prevent lipid peroxidation, usually selenium and tocopherol.
Up-regulation of PPAR-alpha is protective against steatohepatitis and inhibits HCV replication.

PPARα was also reported to be down-regulated by HCV in the liver of infected patients [88, 89]. Since PPARα blocks the replication and production of infectious viral particles, its downregulation likely confers a replicative advantage to the virus in spite of the resulting metabolic disorders for the host cells [90, 91].

PPAR-alpha is upregulated by intracellular peroxidation of DHA, by carbohydrate restriction, and by fasting, as well as by the flavanone naringenin, an antioxidant found in grapefruit, oranges and tomatoes.

From this we might be able to construct a diet that prevents or reverses fatty liver, and thus prevents its sequellae:

· The fats in the diet will be highly saturated; beef and lamb dripping, coconut oil, dairy fats and olive oil, but there will also be optimal amounts of DHA from fish and seafood.

· The diet will supply ample choline, from offal and eggs, and methylation factors B12 and folate from meat and vegetables (spinach and beetroot are excellent sources of the alternative methylation factor betaine).

· Carbohydrate will be restricted (and low GI), caloric intake will not be excessive, and round-the-clock feeding will be avoided.

· The diet will be high in antioxidants. It is important for the activation of PPAR-alpha that DHA peroxidize in hepatocytes and not in the gut or the blood. In this paper vitamin E protects DHA, but I’ve also read that grape seed extract is effective, so we are probably looking at a general antioxidant effect, such as you’d get from a dish like sardines, tomatoes and spinach, cooked lightly in extra virgin olive oil. In the case of hepatitis C, which is a selenium- and zinc-sequestering virus, special attention should be given to the intake of these minerals and moderate supplementation considered.

This letter mentions the intriguing possibility that excess accumulation of NADH is a factor in steatohepatitis. This phenomenon is known as reductive stress and may be relieved by choline, betaine and similar molecules through the generation of methane.

In practice, do such diets work? There have already been a few studies of high-fat diets in fatty liver disease. Considering that these have only covered the carbohydrate-to-fat ratio and ignored choline, PUFAs and antioxidants, the results have been thoroughly encouraging (Note, however, that the average patient changing to an “Atkins-type” diet is likely to eat more eggs than they did before, taking care of the choline angle, and probably more greens and fish).

Dietary Composition and Nonalcoholic Fatty Liver Disease

There were no significant associations between either total caloric intake or protein intake and either steatosis, fibrosis, or inflammation. However, higher CHO intake was associated with significantly higher odds of inflammation, while higher fat intake was associated with significantly lower odds of inflammation. In conclusion, present dietary recommendations may worsen NAFLD histopathology.

The effect of a low-carbohydrate diet on the nonalcoholic fatty liver in morbidly obese patients before bariatric surgery

The findings show that 4 weeks of a very low carbohydrate diet reduces liver fat content and liver size, particularly of the left lobe. This approach may render bariatric surgery or any foregut operations less difficult in morbidly obese patients and may be a useful treatment for nonalcoholic fatty liver disease.

The Effect of a Low-Carbohydrate, Ketogenic Diet on Nonalcoholic Fatty Liver Disease: A Pilot Study

Four of 5 posttreatment liver biopsies showed histologic improvements in steatosis (P=.02) inflammatory grade (P=.02), and fibrosis (P=.07). Six months of a low-carbohydrate, ketogenic diet led to significant weight loss and histologic improvement of fatty liver disease.

Last but not least, some case studies from everyone’s favourite blogger, Stephan Guyenet at Whole Health Source. Stephan is someone who has taken into account choline and all the other factors I’ve mentioned.

Fatty Liver Reversal

Another Fatty Liver Reversal

Another Fatty Liver Reversal, part II

You could make an argument that the pyridoxine form of vitamin B6 is the only really dangerous vitamin supplement. Overdosing on anything else is unlikely if you stick to recommendations, but pyridoxine neuropathy is insidious and persistent and may happen at intakes as low as 200mg/day, and quite possibly lower (case history reporting neuropathy from 100mg/day taken for 10 years).

Axonal pathology is also a feature of the neuronopathies, toxic states in which the primary injuries are found in neuronal cell bodies. This is exemplified by pyridoxine neurotoxicity, where there is sublethal or lethal damage to larger cytons in the sensory ganglia, with failure of such neurons to maintain their axons.

In this brilliant study, the 5 volunteers were the study authors: a detectable neuropathy was induced by a 12mg/Kg/d dosage after 7 months.
However, other factors can increase sensitivity, especially protein deficiency.

Large doses of pyridoxine cause injury to the primary sensory neurons in trigeminal and dorsal root ganglia of animals and patients subjected to megavitamin therapy. The increased hazard to subjects with reduced renal excretory function has been explored previously. In the present work, the neurotoxicity of pyridoxine for rats was found to be increased by dietary protein deficiency. A mere 3 or 7 days of pretreatment with either of two protein-deficient diets were sufficient to accelerate and intensify the clinical neurological signs and histological lesions from pyridoxine injections. These results are caused, at least in part, by loss of body weight, decreased protein binding in serum and decreased consumption of water and decreased volume of urine, which reduce the urinary losses of the toxicant. The vitamers related to pyridoxine (pyridoxal, pyridoxamine) and the coenzyme (pyridoxal 5-phosphate) did not cause clinical signs or lesions similar to those produced by pyridoxine even when injected in maximum tolerated doses. Neither a protein-deficient diet nor bilateral nephrectomy changed the results with the vitamers.

Note that the vitamers (the animal forms of pyridoxine) and the co-enzyme P-5-P (PLP) were not toxic.

I strongly recommend using only vitamin supplements that contain P-5-P or one of the vitamers. A much lower dose can be effective if P-5-P replaces pyridoxine.

The relationship of B6 to protein is important because P-5-P is the coenzyme for most reactions involving amino acid metabolism or catabolism. To make niacin from tryptophan, nitric oxide from arginine, serotinon from tryptophan, cysteine from methionine via homocysteine, these and many more reactions of that type all require P-5-P. It is also required for glycogenolysis and phospholipid synthesis.

Meat, fatty fish, potatoes and bananas are all good B6 sources, but processed meat can be very low in B6 relative to how much protein it supplies. Low B6 status is one of the more common deficiencies detected when populations are studied. Could this be one of the reasons there is always an epidemiological difference between red meat and processed meat? Or could it just be that people who eat processed meats tend to have a greater appetite for, or tolerance of, processed rubbish in general?

The activation of pyridoxine to P-5-P requires riboflavin and magnesium, and deficiencies of these 2 nutrients, deficiencies which are in all conscience common enough (B2 is easily destroyed by UV light) could in theory also sensitize one to pyridoxine toxicity.

There are many features of amino acid metabolism in cirrhosis that suggest that activation of dietary pyridoxine to P-5-P by liver has become inadequate, and/or that the breakdown of P-5-P is excessive.
After administration of pyridoxine there was a significant increase in the plasma PLP level over a 2- to 12-hr period, after which the concentration returned gradually toward the initial value. The area under the concentration/time curve was from 2 to 8 times smaller (P less than 0.002) in the patients with liver disease. To assess possible mechanisms of this change, 5 mg of PLP were intravenously administered to the various patient groups and the pharmacokinetics of the disposition were assessed. The initial and steady state volumes of distribution of PLP were comparable in cirrhotics and controls (P greater than 0.05), but the clearance of plasma PLP in cirrhotics was much faster (63.0 +/- 7.4 versus 31.7 +/- 2.7 ml per min, P less than 0.004). Similar findings were obtained in the other liver disease subjects

There is an inverse association between dietary B6 and deep vein thrombosis.

Our study indicates that low vitamin B6 is associated with an increased risk of recurrent VTE. Until recently, the thrombotic risk associated with low vitamin status was entirely attributed to impaired homocysteine metabolism. But since doubts have been raised about the causal role of homocysteine in thrombotic disease,⁴ other functions of B vitamins need to be considered. Vitamin B6 is a co-enzyme in the metabolism of aminoacids, carbohydrates, neuro-transmitters and lipids,¹² and administration of vitamin B6 inhibits platelet function.¹³ Low vitamin B6 has also been related to elevated C-reactive protein levels and other markers of inflammation,¹⁴,¹⁵. In fact, patients with chronic inflammatory diseases, who are at heightened risk of VTE, exhibit low vitamin B6 levels.¹⁶

From personal experience, I can testify that years of overuse of pyridoxine, especially by someone who is not eating regularly, can result in long-lasting sensory problems even if the doses taken are those normally prescribed or recommended on line. This is not an exclusive problem of the supplement industry, as most of the pyridoxine I have used has been a prescription medication.

Pyridoxine neuropathy is likely to be missed in diagnosis and could even be misdiagnosed as early MS (the difference is that pyridoxine toxicity affects the body symmetrically, MS is asymmetrical). The visual disturbance is interesting and unusual; objects are doubled in the horizontal plane, like watching a 3d movie without the glasses. I still notice this slightly when I look at spires or poles in the middle distance, although the other symptoms have completely cleared, albeit very slowly. Ketogenic dieting was helpful. At one time I could barely read.

Pyridoxine has a fascinating effect on dream recall (very tempting for an opiate addict). Take enough of it, and the very dream changes; a dream that allows you completely perfect recall can be a very vivid but barren dream, with bare floors, little furniture, simple and repetitive architecture, and little in the way of characters or events. The orthomolecular theory is that inability to remember one’s dreams is indicative of pyridoxine deficiency. It is certainly corrected by B6.
Maybe, like DVT, it is caused by a diet too dependent on processed meat and refined carbohydrate.

We’ve had a wonderful summer in New Zealand, with one of the driest Januaries on record. So we Kiwis get out to the beaches as much as we can, soaking up the life-giving rays of the sun and marinating in the surf.

Music: Forever Changes by Love (opens in new window).

We usually drive to get any great distance; in fact we’re high in the stats for vehicle ownership thanks to our acceptance of cheap, excellent quality, second hand Japanese car imports. Consequently the roads get a bit busy and, now and then, unsafe on holidays.

Last Monday was Anniversary Day, and I was driving back to Auckland after enjoying sun and surf at Papamoa near Tauranga. The weather was hot, the road still not so busy, as I cleared the Karangahake Gorge and headed into Paeroa. Suddenly, I found myself in a thick stream of traffic that had slowed to a crawl on the outskirts of Paeroa.

[Digression, for entertainment purposes only. Note the Boer War memorial, the rock on a plinth in the upper right corner. This monument bears two plaques; one to commemorate the consecration of the monument on the date of the coronation of King Edward VII, the other, of equal size, to advise that the coronation was in fact delayed due to illness and to correct the information on the first plaque. Obviously didn't have Twitter in those days. Edward was operated on for appendicitis by Sir Frederick Treves of Elephant Man fame, assisted by Joseph Lister, and made a full recovery. Apropos of the King, as wikipedia states in its inimitable house style:
"The tradition of men not buttoning the bottom button of waistcoats is said to be linked to Edward, who supposedly left his undone due to his large girth.^[9] His waist measured 48 inches (122 cm) shortly before his coronation.^[44] He introduced the practice of eating roast beef, roast potatoes, horseradish sauce and yorkshire pudding on Sundays, which remains a staple British favourite for Sunday lunch."]

To continue:
Some minutes later we could see the cause of this obstruction: a police checkpoint. This would normally be expected to relate to testing for alcohol, or checking vehicles and warrants of fitness for roadworthiness, or investigating a recent crime. Police business.

My car was waved over and stopped. With the clear sense of innocence that comes from imperfect recall, I wound down my window and listened to the police officer.
A campaign against driver fatigue; would we like a bottle of water for each person in the car, and a leaflet on avoiding fatigue? Yes please, and I drive off.

Later I looked at this leaflet. (pdf download). Tips for healthy eating, published by the Accident Compensation Corporation in 2007.

In other words, the New Zealand Police were detaining motorists to give them a leaflet printed by another arm of government, the ACC, that contained “healthy eating” ~~propaganda~~ information that is usually the responsibility of the Ministry of Health. Very interesting.

Now let me just say straight out, I don’t have a problem with the Police doing this. Anything that makes their presence felt on the roads on these holiday weekends reduces the crash rates (I don’t believe there were any serious crashes between Paeroa and Auckland that day), the water was a welcome gift for many, they would be able to weed out really intoxicated drivers or unsafe vehicles or loads through the checkpoint if such appeared, and the “softly softly” approach to policing is good for public relations.

Nor do I have too much of a problem with the leaflet. The “healthy choices” specified are generally more nutritious than the foods they are meant to replace, and even if the message has an anti-fat bias, the fat you’ll find in a donut isn’t its saving grace. My own breakfast that day was fried bacon, eggs, black pudding and tomatoes, and I stayed alert and didn’t get “so hungry” or eat at all till dinner time; which is a contrast to how I used to feel driving long distances on the old “healthy” diet – tired and hungry and somewhat sick.

What interested me most was the sole “scientific” claim in the leaflet.

“A study of a truck fleet showed that the number of serious crashes soared half an hour after the drivers ate fatty or sugary foods”

No reference given. My God, I thought, what truck fleet has so many serious crashes that these sorts of statistics are able to be generated? Whatever they eat, this company sounds like a public menace.
On the face of it, there are other flaws in the argument; most accidents involving trucks are not the trucker’s fault, and there are increased accident rates at certain times of day, due to circadian factors, which may coincide with meals. Did they separate sugar from fat, from starch, from total calories?
The study is mentioned online in terms suspiciously similar to those in the leaflet, but never referenced, and seems to be immune to my normally productive search style. I am only able to learn that it took place in the UK.

This called for a phone call to ACC, then an email to their statistics department, which received a prompt acknowledgement and began a wait for information. Meanwhile, I checked out references to driving safety in David Benton’s “Food for Thought”. Too much or too little blood glucose is associated with accidents. Lowered cholesterol levels (by drug or diet) are associated with a doubled risk of death by vehicle accident, homicide, or suicide (pdf), probably due to increased aggression (I suspect this might not be the case if increased fish consumption caused the drop, but only if it was due to polyunsaturated seed oils, or statins and other drugs).

This would seem to contradict the message in the leaflet if the first part of the lipid hypothesis were to actually be true (I suspect that cholesterol and diet are not so predictably linked at the individual level).

Less fatigue in the short term perhaps, but more aggression and self-harm on our roads as healthy eating works its dark magic over time.

My advice for safe driving would be to avoid foods that cause blood sugar slumps (refined starch and sugar), skip anything deep fried, go for a little protein (cold meat, smoked fish, boiled eggs, cheese), raw vegetables and fresh fruit if you’re hungry on the road. Eat a filling breakfast like I did but otherwise don’t fill’er’up till you get where you're going. Drink plenty of water, if for no other reason than to make you stop and stretch your legs whenever you pass a toilet. Drink coffee, black or with cream, rather than uber-sweet energy drinks, but not too much too soon . And, over the longer haul, unless you are under the care of a competent cardiologist for good and proper reasons (perhaps time to reconsider whether you should be driving precious or heavy loads on long trips at all), avoid the temptation to tamper with your “cholesterol”. That’s a form of self-abuse with the potential to lead to mental and physical degeneration.

Look, I’m no Zoe Harcombe. I’m not even very good at math, so I’m not going to wait till the study arrives and post the analysis that’s been lacking, I’m just going to post this review of the leaflet. When the study turns up, I’ll link it and discuss it in the comments section of this post. The thing I find interesting here is the insight into how government departments turn epidemiology into action (or, perhaps, how they select epidemiology that supports actions decided on for other reasons). As I said, I don’t have much of a beef with the pamphlet itself (except for the sloppy citation).

“The results show that the omega-6 linoleic acid group had a higher risk of death from all causes, as well as from cardiovascular disease and coronary heart disease, compared with the control group.”

We should be most skeptical of the research that best confirms our own beliefs. It may not contain an inaccurate result – in the case of the Sidney Diet Heart Study, the result is consistent with the totality of the evidence that is appearing from other sources – but it may not be as convincing to others as it appears to us. We should always be alert to the desirability of designing experiments to produce results that, one way or the other, will convince any reasonable person. In diet studies this may well be unattainable, and usually the “expert evidence” of clinical studies has to be considered in the context of circumstantial and eyewitness evidence from other sources, but it is the scientific ideal.

On the BMJ website where the study appears, doctors can send in their responses, and some of these responses give cogent reasons why a reasonable person, especially one not engaged with the Paleo discussion of seed oils over the past few years, might remain unconvinced by the latest revelations.

Perhaps the best response comes from Professor Jean Gutierrez, assistant professor of exercise science at Washington University. She points out that one of the products used in the trial probably contained high levels of trans fats:

Participants in the intervention group consumed “Miracle” Margarine, a product based on safflower oil. Hydrogenation of safflower oil itself creates a grainy product low in linoleic acid, so high-linoleic safflower oil margarine products were created by blending liquid safflower oil with another hydrogenated oil stock (3). Miracle Margarine used in the original study was either low in linoleic acid (due to hydrogenation of the safflower oil itself) or the oil was blended with another commercially hydrogenated fat to create a plastic margarine product. An investigation by Bernfeld, Homburger, & Kelley, published in 1962, indicated that the fatty acid composition of most margarines of the time were about 50-60% 18:1 monounsaturated fats (including oleic and trans isomers) and about 20-30% 18:2 linoleic acid, even in those products having high-PUFA claims on the label (4). None of the 22 margarines studied had a majority of fatty acids coming from PUFA. Another report from the same time period indicates that commercially produced hydrogenated fats, like those added to safflower oil to make margarine, were generally composed of about 25-40% trans fats (5). Fatty acid composition of margarines in the 1960s investigation were not comparable to liquid vegetable oil, despite package claims. The only reference supporting the healthful content of Miracle Margarine is a very general press release from the company who made the product (6). It is probable that Miracle Margarine had significant trans fatty acid content.

This is an obvious confounder, hard to dispute on science grounds. Morally it might not make much difference; if advice to reduce saturated fat and increase PUFA consumption lead to the use of such dodgy products such as Miracle Margarine, as it did, then it still stands condemned historically. Have there been studies where oil but not margarine was the intervention? Was the Rose Corn Oil Study really just a study of corn oil? Comments section please.

In the section "other dietary considerations" it appears that the "prudent diet" intervention group avoided the ordinary margarines allowed in the diet of the controls. We will probably never know which group ate most trans fats. The fact that the intervention group had low cholesterol and trans fats are supposed to elevate LDL cholesterol does seem to indicate that any harm trans fats may have done was not due to "lipid hypothesis" mechanisms.

Having established her scientific objectivity by drawing attention to the study’s biggest flaw, Professor Gutierrez strikes a home run with her last paragraph:

In addition to increasing PUFA intake, participants in the intervention group reported reduced dietary saturated fat, cholesterol, and calorie intake from baseline. A negative energy balance was verified with a slight mean drop in BMI. As expected, circulating total cholesterol and triglycerides were reduced in the intervention group, but mortality outcomes were not improved consequent to these circulating lipid and anthropometric changes, which is unexpected and interesting. The more important question arising from this study may be why a dietary intervention that improved all of these commonly used surrogate end points did not reduce all-cause mortality?

Why indeed, the world wonders.

Surgeon Basil D Fadipe from Dominica has an explanation for the result:

In a nutshell, the study shows LA is a 'substrate' for oxidative stress convertible to toxic derivatives, mechanistically adverse to the cardiovascular-coronary integrity; An otherwise good dietary item, LA's bad company (smoke/alcohol) wrecks its good potential.

This view has some merit – LA plus alcohol is definitely destructive to the liver via these mechanisms, and there are clearly links between high alcohol consumption and the negative effect of LA in the study (though it doesn't seem that abstinence removes the risk), but it does seem like special pleading. People will be exposed to oxidative stress in various ways, not all easily predicted or avoided. Why consume a dietary item that magnifies this insult in quantities greater than those required for essential functioning?

UK GP William K. Neville sums up the Paleo view;

Linoleic acid is an omega 6 fatty acid. It causes weight gain and inflammation. Omega 3 fats have the opposite effect. The ideal ratio of omega 6 to omega 3 in the diet is about 2:1 [9]. Modern diets have a ratio of 20:1 due to the false belief that linoleic acid is good for us. In pre-historic times weight gain from eating omega 6 fats in nuts and seeds, which were plentiful in the autumn, was an advantage to prepare humans for winter [10]. Meat from grass fed animals has a good amount of omega 3. But 99% of farmed animals are fattened on grain products such as brewery waste prior to slaughter which lowers their omega 3 levels to zero and the meat contains only omega 6. Similarly, farmed fish has reduced omega 3 levels due to being fed on grains.

Heart disease was rare before the introduction of industrial seed oils at the start of the 20th century [11]. Four meta-analyses recently prove saturated fat to be harmless [12]. The lesson of this article is that it is time we stopped demonising the really healthy fats such as butter, lard, beef dripping, coconut oil and palm oil [13, 14].

He makes more of the case against dairy than is perhaps justified by the evidence to date when he says:

The most important oxidising agent of LDL particles is the peptide BCM-7 produced by the digestion of A1 milk. The level of A1 milk consumption in countries is directly proportional to the rate of heart disease. Milk in the UK is mostly A1. Milk in Africa is mostly A2. France is in between. A few supermarkets have recently begun to sell A2 milk which has the potential to prevent many diseases such as type 1 diabetes and heart disease [6, 7, 8].

All I can say is that A2 milk tastes better, but is just as allergenic for my purposes. Milk is a complex food and there is no one factor that applies to everyone, but the BCM7 case outlined in “The Devil in the Milk” deserves study. I expect there are many other things that correlate with heart disease just as well as A1 milk does. Consider though, that when you eat meat, you eat from one or maybe two animals (unless it’s processed sausage meat). When you drink milk, the milk from large numbers of animals has been combined, each with its distinctive immunological factors. Our milk-drinking ancestors, if we had them, probably drank from one or two cows at a time. My granddad used to say that one secret of health was not to mix one’s drinks.

American Physician Megan I. Maurer makes a valid point that will also appeal to Paleo dieters:

I would like to point out that the source of the omega-6 fatty acids in this case was from safflower oil and safflower oil margarines which, despite being high in omega-6 fatty acids are still very calorically dense and in my opinion are not representative of what you might see had they used a whole food course of omega-6 fatty acids, such as sunflower kernels or walnuts. It has been consistently shown that a whole-food plant-based diet offers great cardiovascular protection. I think a study showing increased intake of omega-6 fatty acids in their whole form vs. saturated fats would have been more telling than just replacing it with oil.

Of course a diet of walnuts (an omega-3 nut, in fact) and sunflower seeds will introduce other confounders. But a worthwhile experiment would be to replace fatty meats with nuts and seeds, and butter and cooking fats with spreads and oils. The difference between intrinsic and extrinsic fats may be as important a confounder as the difference between intrinsic and extrinsic sugars.

The question is, more studies are needed, but are they ethically justified? It’s easy to test a dietary change when the evidence one has seen and the theories that seem to make most sense suggest it’ll be beneficial. Is it right to continue to experiment in this way as the evidence of harm accrues?
You might suspect it was the trans fats in the margarine that caused those extra deaths, but would you be prepared to re-run the study without them to find out?

However, the fact is that the experiment has overtaken our society and most of us have been enrolled in it, despite the actual results from the Sidney Diet Heart Study proper having been “lost” since 1973.

If PUFAS do have some potential for good instead of evil in certain cases, can we avoid discarding the baby with the bathwater? In 2009 Stephan Guyenet analysed a 1994 study that compared the so-called “prudent diet” used in Sydney with a diet that supplied limited omega-6 in the context of adequate omega-3; the Lyon Diet Heart Trial. He writes:

Here's where it gets interesting. The intervention group ate three times as much omega-3 alpha-linolenic acid as the control group, and 32% less omega-6 linoleic acid. The ratio was 20 : 1 linoleic acid : alpha-linoleic acid in the control group, and 4.4 : 1 in the intervention group. This was due to the combination of a low-fat diet and the canola oil goop they were provided free of charge.

But it gets even better. The intervention group reduced their omega-6 linoleic acid intake to 3.6% of calories, below the critical threshold of 4%. As I described in my recent post on eicosanoid signaling, reducing linoleic acid to below 4% of calories inhibits inflammation, while increasing it more after it has already exceeded 4% has very little effect if omega-3 is kept low*. This is a very important point: the intervention group didn't just increase omega-3. They decreased omega-6 to below 4% of calories. That's what sets the Lyon Diet-Heart trial apart from all the other failed diet trials.

After five years on their respective diets, 3.4% of the control (prudent diet) group and 1.3% of the intervention ("Mediterranean") group had died, a 70% reduction in deaths. Cardiovascular deaths were reduced by 76%. Stroke, angina, pulmonary embolism and heart failure were also much lower in the intervention group. A stunning victory for this Mediterranean-inspired diet, and a crushing defeat for the prudent diet!

There's a little gem buried in this study that I believe is the other reason it didn't get accepted to the New England Journal of Medicine: there was no difference in total cholesterol or LDL values between the control and experimental groups. The American scientific consensus was so cholesterol-centric that it couldn't accept the possibility that an intervention had reduced heart attack mortality without reducing LDL. The paper was accepted to the British journal The Lancet, another well-respected medical journal.

[implications of the study here]

So in both the Sydney study and the Lyon trial, total cholesterol and LDL cholesterol had nothing to do with whether participants lived, or died of heart disease. Of course the Lyons “Mediterranean” diet only outperformed the “prudent” diet; the controls in the Sidney Diet Heart Study already seem to have done that by eating as people normally did in Sidney between 1966 and 1973.

The last word goes to Professor Dhastagir S. Sherrif of Benghazi University, Lybia:

Polyunsaturated fatty acids (PUFA) are essential fatty acids to be supplied in the diet. These are important for membrane function, producing eicosanoids; the endocannabinoids, the lipoxins and resolvins form lipid rafts for cellular signaling, act on DNA, activating or inhibiting transcription factors such as NF-κB - playing a vital role in physiological functions of the body. Yet there needs to be a balance between its intake and the form of PUFA taken in the diet.

Being polyunsaturated, they generate free radicals, cause lipid peroxidation and damage mitochondrial function. It is suggested that the intake of PUFA must be accompanied by adequate amounts of intake of anti-oxidants such as vitamin E. Human body and its metabolism cannot be viewed as parts but as whole body metabolism. Whole body metabolism needs to be viewed with the interplay of internal and external factors that regulate and maintain homeostasis. Extracellular factors including the dietary constituents need to be balanced with the internal physiological milieu unique to every individual. We need to remember the Daedalus effect: for every remedy there is an adverse side effect. How we balance them is the duty of true science that will help promote health.

This study on supplement use hasn't come up on the paleo radar, but it's a good example of how to expose junk epidemiology. It's from the Orthomolecular Medicine News Service - you can subscribe here and it's well worth doing, they don't mail often and are in the process of becoming accepting of low-carb science (such as ketogenic diets for cancer) while trying to cling to the saturated fat is bad, only vegetables and supplements are healthy message. Because these are not stupid people, and they already have methods that work, it's an interesting struggle to follow. Their archives link is here.
It's another junk study from Sweden - what is it about those Swedes? Is it a case of scientific suevism?
I love that he refers to Bayesian analysis as the way to proceed in these cases. I'm no mathematician, but it makes sense to me.

At the foot of the page I've included an abstract from a review of vitamin C for prevention of Complex Regional Pain Syndrome. This is an impressive result; 0.22 relative risk of this debilitating after-effect of fracture surgery from supplementing 500mg or more ascorbic acid daily for 45-50 days. An unusually effective clinical use for any supplement.
While the authors of the various trials cite the antioxidant effect of ascorbic acid and the toxicity of ROS as a mechanism, I suspect that improved integrity of the collagen matrix in the early stages of bone regrowth might also account for these benefits. After all, that's why ascorbic acid is a vitamin.

Music; Intermezzo from Cavalleria Rusticana by Pietro Mascagni.

Cataracts and Vitamins: The Real Story

by Damien Downing, MBBS, MSB, and Robert G. Smith, PhD

(OMNS Mar 5, 2013) "Hidden danger of everyday supplements is revealed" blared the headline in the UK Daily Mail [1] - a newspaper that is well known for declaring that, for example, "coffee causes cancer" and "coffee reduces cancer risk" on different pages of the same issue. This time it is reporting on a study out of Sweden that appears to show that taking vitamin C or vitamin E supplements increases your risk of developing a cataract - by about 20% for C and 60% for E. [2] It makes a good headline, but does it make sense?

Is this research?

No. They didn't give anybody anything, or do anything to them, This was just a computer exercise in which they re-analyzed postal questionnaires sent to the entire male population aged between 45 and 79 in an area of Sweden, and matched the responses to another database of cataract operations. Although the title says that it is "a population-based prospective cohort study," prospective would really mean that they followed the group of subjects, the cohort, closely over a period of time, without losing many of them. In fact they simply had their computer go through some old electronic records. Nobody was interviewed, and no checks or validation exercises were carried out. No researcher met any of the men in the study, ever.

Is it reliable?

No. The first really serious shortcoming of this paper, the gorilla in the room, is that half the men never replied in the first place, and then the authors deliberately excluded a lot more for reasons such as diabetes - one of the other main "outcomes" of the study and a big risk factor for cataracts. Finally, they omitted to account for another few thousand people, so that in the end they were only studying 27 percent of the original population. If they had randomly selected this sample of the population that would be fine, but in fact the subjects selected themselves by bothering to fill in and return the questionnaire, or not. What were their reasons? We know not. That means that already several types of selection bias have been introduced, and all the results are now meaningless.

There could even be what's known as indication bias - when cause and effect get mixed up. So, for instance, cataracts can take decades rather than years to develop, and people with early symptoms might be more likely to take supplements to ease their eyestrain. If the study goes on entirely in a computer, there's no way of telling.

Is it scientifically plausible?

No. The study contradicts many other studies that have shown either no effect or actual benefits of vitamin C and E for preventing cataracts and other eye diseases. Cataracts are common among older people, and it is well known that antioxidants can reduce the risk of developing them if taken long-term. Smoking, obesity, and diabetes are well-known risk factors for cataracts, and antioxidants are known to prevent the damage caused by these factors. [References below]. In one study, vitamin C supplements taken over 10 years or more reduced the risk of cataracts by about 80%.This is a huge dose-related effect, strongly suggesting the benefit of antioxidants in preventing cataracts. The effect was not apparent for short-term use, suggesting that any shorter-term study may not identify the benefit. (Jacques et al, 1997).

Studies should not be viewed in isolation, because that leads to the "coffee causes cancer" and "coffee reduces cancer risk" absurdity. The effect of a discrepant study such as this is to marginally adjust the current information about risk. Let's say that based on previous studies, as listed below, we thought there was an 80 percent probability that taking vitamins would help to prevent cataracts; after this one we might revise that to 75 percent. This is known as Bayesian probability [after an English minister 300 years ago] and makes a whole lot more sense than the supposedly black-and-white, 95% confidence-interval type of statistics used here. If a gambler isn't a Bayesian he's an idiot; every hand, every throw, alters the odds. So does every study.

The conclusions here are also dodgy because there is no real data on the amounts of the vitamins taken - only a guesstimate from an earlier study of 248 men - and even occasional use was tabulated as use of supplements. For this to make a substantial difference to the health outcome isn't really plausible.

So, in real life?

To prevent age-related diseases of the eye including cataracts, the best current advice is to lower oxidative stress by stopping smoking, reduce excess weight (diabetes again), eat an excellent diet along with a multivitamin supplement and additional supplements of vitamin C (3,000 - 6,000 mg/day in divided doses), vitamin E (400-1,200 IU of natural mixed tocoperols and tocotrienols). This will greatly help prevent oxidation of the tissues of the eye. Artificial forms of vitamin E (dl-alpha-tocopherol) are only 50% as biologically active as the natural form (d-alpha-tocopherol). Taking alpha-tocopherol alone is thought to lower the effective uptake of the other beneficial forms of vitamin E, so it's important to take the natural form of mixed (alpha-, beta-, gamma-, delta-) tocopherols.

(Dr. Damien Downing is a practicing physician specializing in orthomolecular medicine in London, UK, and Dr. Robert G. Smith is a neurophysiologist specializing in eye research at the University of Pennsylvania.)

(I don't have a picture of a Swedish epidemiologist, so here's a Swedish battleship. Technically a Sverige class coastal defense ship, a small battleship of limited speed and range built for defending Sweden's shoreline and harbours.)

References:

1. http://www.dailymail.co.uk/health/article-2283178/How-vitamin-pills-raise-risk-cataracts-hidden-danger-everyday-supplements-revealed.html

2. Selin JZ, Rautiainen S, Lindblad BE, Morgenstern R, Wolk A High-Dose Supplements of Vitamins C and E, Low-Dose Multivitamins, and the Risk of Age-related Cataract: A Population-based Prospective Cohort Study of Men (2013) American Journal of Epidemiology, published online. DOI: 10.1093/aje/kws279

Vitamin C lowers cataract risk:

Head KA. Natural therapies for ocular disorders, part two: cataracts and glaucoma. Altern Med Rev. 2001 Apr;6(2):141-66. [vitamin C alone or with vitamin E reduces risk of cataracts]

Jacques PF, Taylor A, Hankinson SE, Willett WC, Mahnken B, Lee Y, Vaid K, Lahav M. Long-term vitamin C supplement use and prevalence of early age-related lens opacities. Am J Clin Nutr. 1997 Oct;66(4):911-6. [Huge effect, 77% - 83% decrease in lens opacities]

Vitamin E lowers cataract risk:

Rouhiainen P, Rouhiainen H, Salonen JT. Association between low plasma vitamin E concentration and progression of early cortical lens opacities. Am J Epidemiol. 1996 Sep 1;144(5):496-500.

Nourmohammadi I, Modarress M, Khanaki K, Shaabani M. Association of serum alpha-tocopherol, retinol and ascorbic acid with the risk of cataract development. Ann Nutr Metab. 2008;52(4):296-8. doi: 10.1159/000148189.

Seth RK, Kharb S. Protective function of alpha-tocopherol against the process of cataractogenesis in humans. Ann Nutr Metab. 1999;43(5):286-9.

Engin KN. Alpha-tocopherol: looking beyond an antioxidant. Mol Vis. 2009;15:855-60. [ vitamin E likely plays a role in preventing cataracts]

Smoking increases risk:

Mosad SM, Ghanem AA, El-Fallal HM, El-Kannishy AM, El Baiomy AA, Al-Diasty AM, Arafa LF. Lens cadmium, lead, and serum vitamins C, E, and beta carotene in cataractous smoking patients. Curr Eye Res. 2010 Jan;35(1):23-30. doi: 10.3109/02713680903362880.

Hiller R, Sperduto RD, Podgor MJ, Wilson PW, Ferris FL 3rd, Colton T, D'Agostino RB, Roseman MJ, Stockman ME, Milton RC. Cigarette smoking and the risk of development of lens opacities. The Framingham studies. Arch Ophthalmol. 1997 Sep;115(9):1113-8.

Healthy diet prevents cataracts:

Mares JA, Voland R, Adler R, Tinker L, Millen AE, Moeller SM, Blodi B, Gehrs KM, Wallace RB, Chappell RJ, Neuhouser ML, Sarto GE; CAREDS Group. Healthy diets and the subsequent prevalence of nuclear cataract in women. Arch Ophthalmol. 2010 Jun;128(6):738-49. doi: 10.1001/archophthalmol.2010.84.

Williams DL. Oxidation, antioxidants and cataract formation: a literature review. Vet Ophthalmol. 2006 Sep-Oct;9(5):292-8.

2013 Jan-Feb;52(1):62-6. doi: 10.1053/j.jfas.2012.08.003. Epub 2012 Sep 15.

Efficacy and safety of high-dose vitamin C on complex regional pain syndrome in extremity trauma and surgery--systematic review and meta-analysis.

Shibuya N, Humphers JM, Agarwal MR, Jupiter DC.

Source

Texas A&M Health and Science Center, College of Medicine, Temple, TX, USA. shibuya@medicine.tamhsc.edu

Abstract

Complex regional pain syndrome (CRPS) is a devastating condition often seen after foot and ankle injury and surgery. Prevention of this pathology is attractive not only to patients but also to surgeons, because the treatment of this condition can be difficult. We evaluated the effectiveness of vitamin C in preventing occurrence of CRPS in extremity trauma and surgery by systematically reviewing relevant studies. The databases used for this review included: Ovid EMBASE, Ovid MEDLINE, CINAHL, and the Cochrane Database. We searched for comparative studies that evaluated the efficacy of more than 500 mg of daily vitamin C. After screening for inclusion and exclusion criteria, we identified 4 studies that were relevant to our study question. Only 1 of these 4 studies was on foot and ankle surgery; the rest concerned the upper extremities. All 4 studies were in favor of this intervention with minimal heterogeneity (Tau(2) = 0.00). Our quantitative synthesis showed a relative risk of 0.22 (95% confidence interval = 0.12, 0.39) when daily vitamin C of at least 500 mg was initiated immediately after the extremity surgery or injury and continued for 45 to 50 days. A routine, daily administration of vitamin C may be beneficial in foot and ankle surgery or injury to avoid CRPS. Further foot and ankle specific and dose-response studies are warranted.

http://www.ncbi.nlm.nih.gov/pubmed/22985495

(Our first song for today is appropriately Junk by The Puddle, a early post on this topic from 1985.)

Naltrexone is a mu-endorphin antgonist that is used as an opioid antagonist. It will reverse intoxication from opioid analgesics and has a longer duration of action than naloxone. Naloxone is preferred in emergency settings because of its faster onset of action, but naltrexone, unlike naloxone, is effective given by mouth, and its long duration of action (10 hrs) makes it a safer treatment for overdose with long-acting opioids such as methadone (24 hrs, but the half-life of methadone can be significantly decreased by urinary acidifiers such as ascorbic acid or citric acid, and is increased by urinary alkalizers such as sodium bicarbonate as methadone has low solubility at high urinary pH). Naltrexone's most common clinical use is in doses of 50mg daily as a maintenance treatment to blockade the addictive effects of both opiates and alcohol. Recently I spoke to an AOD patient using naltrexone in this way and was surprised that they reported that the drug had an anti-depressant effect. This isn't what would we'd expect under the old endorphin receptor model from a full-time blockade; dysphoria would be the predicted side-effect.

A clue lies in the popular off-label use of naltrexone at low doses (1.25-2.5 mg nocte) as an immune-modulating agent. The Low Dose Naltrexone homepage claims

"FDA-approved naltrexone, in a low dose, can normalize the immune system — helping those with HIV/AIDS, cancer, autoimmune diseases, and central nervous system disorders."

This is not quackery; read the NOLA Hepper blog in the blogroll to your right for a case study of LDN in the treatment of hepatitis C. Naltrexone is some potent juju, but the results have been hard to explain till recently. The mechanism that was originally stated is as followed; endorphin synthesis is highest at night. Blocking receptors for a few hours while the patient sleeps has the effect of elevating endorphin levels; these elevated endorphins have mood and immune-modulating effects. Hormesis in other words.

"The brief blockade of opioid receptors between 2 a.m. and 4 a.m. that is caused by taking LDN at bedtime each night is believed to produce a prolonged up-regulation of vital elements of the immune system by causing an increase in endorphin and enkephalin production. Normal volunteers who have taken LDN in this fashion have been found to have much higher levels of beta-endorphins circulating in their blood in the following days. Animal research by I. Zagon, PhD, and his colleagues has shown a marked increase in metenkephalin levels as well."

The endorphin effects of naltrexone are significant of course, but the much higher dose taken by the patient I spoke to could not work in this way; also, both opioid drugs like morphine, and morphine withdrawal states have been found to stimulate HCV replication in vitro.

Recently, beginning in about 2010, studies started to appear showing that opioids and opoid antagonists have TLR-4 activity. TLR-4 is a PAMP (pathogen associated molecular pattern) receptor. TLRs tell immune cells what type of pathogens they may (or may not) need to get agitated about. In the case of TLR-4 this is gram-negative bacteria, and the ligand is lipopolysaccharide (LPS).

Except that pathogens aren't the only organisms to produce TLR-4 ligands; probiotics, saprophytes and other benign or beneficial bacteria can also have TLR-4 activity, and this exposure is associated with lower rates of auto-immune disease, allergies, depression, cancer and great deal else besides through the "Hygiene hypothesis" or "Old Friends hypothesis" (there are some good articles on this at Emily Deans' Evolutionary Psychiatry blog linked in my blogroll on the right hand side of the page).

The effects we would expect to see from TLR-4 activation by what I might term FAMPs (friend associated molecular patterns) if the Old Friends hypothesis is correct are the same ones attributed to LDN (which increases TLR-4 expression). The illnesses LDN is claimed to treat are all diseases that have come into prominence in the wake of microbiotal extinctions. In many cases they barely seem to have existed prior to the widespread use of antibiotics, disinfectants, and antithelmetics.

2012 Mar;26(3):480-8. doi: 10.1016/j.bbi.2011.12.010. Epub 2012 Jan 5.

Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages.

Franchi S, Moretti S, Castelli M, Lattuada D, Scavullo C, Panerai AE, Sacerdote P.

Source

Dipartimento di Farmacologia Chemioterapia e Tossicologia medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy.

Abstract

Opioids have been shown to affect both innate and adaptive immunity. We previously showed that morphine affects the macrophage production of pro-inflammatory cytokines after LPS in a NFkB dependent manner.
Toll like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkB activation. TLR4 is considered the Lipopolysaccaride (LPS) receptor.
The data here presented show that, in murine macrophages, morphine impacts on the immune function acting on the early step of pathogen recognition. Morphine, when added to RAW 264.7 cells and when injected into mice (s.c. 20mg/kg) is in fact able to decrease TLR4 both at mRNA and protein level in RAW cells and peritoneal macrophages. In the same cells, the mu opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation. The effect of the two drugs is moreover lost in case of co-administration.
Experiments with MOR KO mice and with DAMGO (MOR specific agonist) confirm that the effect of morphine on TLR4 mRNA in peritoneal macrophages is due to the MOR activation. Moreover the effect on TLR4 is blocked by PTX thus indicating the involvement of a G(i) protein after MOR binding. This work unveils a clear link between MOR activation and TLR4, suggesting a new possible mechanism at the basis of the peripheral immunosuppressive effect of opioids.

Make no mistake, this is edge-of-your seat scientific stuff that for my money is predictive of rapid medical progress in unexpected directions. For example: Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. In other words, some of the anti-addictive effect of naltrexone blockade is due to its TLR-4 agonism, not its mu-endorphin antagonism (though the two are probably indirectly connected). One obvious implication of this research is that the dose range for both LDN and addiction treatment should probably be much wider. Some people will need larger doses or more frequent dosing for LDN to work (or even smaller doses; VLDN treatment has been used to suport methadone withdrawal), while AOD patients who do not tolerate 50mg naltrexone may well benefit from lower doses. The dose thresholds for endorphin and TLR-4 effects are likely to be different and to vary between indviduals.
Exciting - nay, exhilarating. Sometimes you just gotta love science. It's one of those gifts that just keeps on giving.

(more music - Steely Dan "My Old School")

The naltrexone story I covered in the last post has turned up other insights into its mode of action in Hepatitis C.

(music: Steely Dan live from 1974)

Most importantly, naltrexone is antifibrotic. TLR4 agonism stimulates the activation of hepatic stellate cells (HSC) into myofibroblasts that lay down collagen-rich matrix all over the place like a one-armed plasterer on meth. A little of this is part of the repair process but excess is like DIY repairs gone bad. Sooner or later there's so much plaster you can't get in or out of your own cells. Hilarity doesn't ensue.

Mechanisms of Hepatic Fibrogenesis

Among the most compelling pathways of injury are those recently uncovered for innate immune signaling in liver. Specifically, the discovery of TLRs has led to major advances in understanding how the human organism responds to pathogens. The identification of TLR4, the receptor for bacterial lipopolysaccharide, on Kupffer cells, was therefore not a surprise, but its expression on stellate cells was unexpected. Moreover, although TLR4 signaling in macrophages may be essential for inflammatory responses, recent studies have indicated that signaling by stellate cells in response to lipopolysaccharide and possibly endogenous ligands of TLR4 (eg, high-mobility group box 1, biglycan, and heparan sulfate) may be more important than in Kupffer cells in eliciting a fibrogenic response by down-regulating bone morphogenic protein (BMP) and activin membrane-bound inhibitor, a transmembrane suppressor of transforming growth factor β1 (TGFβ1), which is the major fibrogenic cytokine in the liver. This finding has converged with evidence that specific single-nucleotide polymorphisms of TLR4 contribute to the rate of fibrosis progression in HCV infection, thereby linking a genetic risk marker to disease pathogenesis.

Naltrexone prevents gliosis (inflammation of neuroglial cells) caused by opiates through TLR4 agonism. HSCs are hepatic glial cells. Glial cells are "caretaker" cells that protect and repair nerves, blood vessels and the like and maintain the appropriate spaces between cells and the extra-cellular matrix. So this link between gliosis and fibrosis doesn't surprise me. Even in the dizzying and scarcely ever linear world of immunology, sometimes the correct answer can be the simplest.

What are the relevant TLR4 agonists in liver fibrosis? Lipopolysaccharide (LPS) from gram-negative bacteria, and alcohol. Opiates too maybe (methadone use is associated with fibrosis in Whites Only in this study, but methadone can always be either substituting for, or encouraging the use of, something worse).

Naltrexone antagonizes TLR4 and increases receptor numbers (decreasing sensitivity).

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats

This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.

Comparative Study between the Effect of Atorvastatin and Naltrexone on Hepatic Fibrosis Induced by Bile Duct Ligation in Rats (pdf)

Another TLR4 antagonist seems to be the polysaccharide-A from astragalus root. Astragalus is a common Chinese herb which is well-tolerated and used in many anti-inflammatory preparations including liver-protecting and immune-boosting formulas. I like it myself and have had good results with either astragalus alone, or a mixture of astragalus and the super-weird cordyceps fungus, which also contains an active polysaccharide but much else besides.

TLR4 expression in chronic UTI patients after astragalus treatment was higher than pre-treatment.

The pattern with these agents seems to be that sensitivity to "bad" LPS is reduced, but that macrophage activity is enhanced. This should see some clearing of the immune complexes (cryoglobulinaemia) associated with hepatitis C and a reduction in the various extra-hepatic autoimmune symptoms they cause. Hepatic LPS sensitivity is also reduced by the presence of highly-saturated fats in the diet (beef tallow, coconut oil, etc) and the restriction of polyunsaturated fatty acids.

Probiotics (such as the anti-inflammatory Rhamnosus LGG) have a comparable effect on TLR4: activation after LPS exposure is decreased.

LGG attenuates LPS induced inflammation, and this may be associated with TLR4/NF-κB down-regulation.

Lactobacillus GG Treatment Ameliorates Alcohol-induced Intestinal Oxidative Stress, Gut Leakiness, and Liver Injury in a Rat Model of Alcoholic Steatohepatitis

I think it's a good idea to take probiotics if you have hepatitis C, and the L. Rhamnosus plus Reuterii combination was my favourite long before I knew this TLR immunology stuff.
J Am Coll Nutr. 2012 Feb;31(1):14-23.
Probiotics in the treatment of the liver diseases.
Kirpich IA, McClain CJ.

Source

Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, KY 40202, USA.

Abstract

The concept that interactions between the gut, the liver, and the immune system play an important role in liver diseases is an old concept that has recently seen a resurgence in interest. Altered intestinal bacterial flora and gut-associated endotoxemia are increasingly recognized as critical components in both nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Probiotics have been proposed in the treatment and prevention of many conditions, including the liver diseases. Probiotics are live microorganisms that, when consumed in adequate amounts, confer a health benefit to the host. There are many mechanisms by which probiotics enhance intestinal health and influence the gut-liver axis, including modulation of the intestinal microflora, modification of intestinal barrier function, and immunomodulation. The present review summarizes the recent studies highlighting the role of the intestinal microflora in the development of NAFLD and ALD and the potential efficacy of probiotics as a therapeutic strategy for liver diseases.

Oh, BTW, what's another TLR4 antagonist? Niacinamide (nicotinamide). I've told you that's antifibrotic in an earlier post, for quite different reasons.
I could go on all day, all year maybe, but I have stuff to do now.

Cordyceps in action (The one in this video is a relative of C. Sinensis, the herbal one, which parasitizes Tibetan moth larvae):

One of the very minor controversies in Paleo-land is whether algal foods or supplements are healthful. For what it's worth, pond algae appeared in the Paleolithic menu (according to the 2008 book Feast: why humans share food by Martin Jones). Spirulina and Chlorella supplements have both been used in the treatment of Hepatitis C with interesting results:
(music - Free Kim Dotcom by The Puddle featuring Matthew Bannister)

Efficacy and safety of Chlorella supplementation in adults with chronic hepatitis C virus infection http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581996/

Eighteen adults with chronic infection by HCV genotype 1 received daily oral supplementation of Chlorella for 12 wk. Changes in the RNA levels of HCV, as well as those of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were evaluated following this treatment period. Paired t tests were conducted to compare the means of the different variables at the beginning and end of the study. Side effects and quality of life aspects were also compared between weeks 0 and 12 of the study period.

RESULTS: A majority 84.61% of the patients had a significant decrease in their ALT levels from week 0 to week 12. Evaluation of side effects showed that Chlorella was well tolerated. Quality of life assessment showed that 76.9 of the participants reported an improvement in their energy levels and 46.1% reported an improvement in their perception of general health. Although 69.23% also showed a decrease in their AST levels, this was not statistically significant. Most patients that exhibited an improvement in their ALT and AST levels also showed a tendency toward a decreased HCV viral load. The HCV RNA levels showed a decrease in 69.23% of the patients, which along with changes in AST/ALT ratios from week 0 to week 12, these results were not statistically significant.

One very interesting outcome, not captured in the abstract was that those subjects who had not undergone previous treatment with interferon almost all (5/6) saw significant drops in viral load, whereas the 7 subjects that had previously used, and failed to respond to, interferon had no such reaction (see Table 1).

What effect of algae could account for these results? Both spirulina and chlorella express PAMPs (Braun polysaccharides in the case of spirulina, and glycoprotein in the case of chlorella) that possess activity at TLR2. TLR2 is interesting because, as well as its immune system signalling role, it also promotes the intestinal detoxification of benzopyrene carcinogens. But that curious fact need not concern us here.

[One hundred years ago the birth of immunology was made official by the Nobel Prize award to Elie Metchnikoff and Paul Ehrlich. Metchnikoff discovered phagocytosis by macrophages and microphages as a critical host-defense mechanism and thus is considered the father of cellular innate immunity. He also was interested in the impact of normal flora on well-being and in pre- and probiotic diet and their influence on the normal flora. Ehrlich described the side-chain theory of antibody formation and the mechanisms of how antibodies neutralize toxins and induce bacterial lysis with the help of complement and thus is considered one of the fathers of humoral adaptive immunity.]

TLR2 activation by algal ligands activates elements of the innate immune system; natural killer T cells (NKT) and interferon (PDF). This will be responsible for the drops in viral load (in people whose immune systems are not already either unresponsive to interferons, or damaged by exposure to the supraphysiological levels of interferon-alpha used in HCV therapy).

HCV core protein is a pro-inflammatory TLR2 ligand; this allows the immune system to recognise the virus and respond appropriately. Most HCV exposures (antibody+) will be cleared in the first 6 months, but chronic infection means that the virus has managed to subvert these responses. So supplying algal TLR2 ligands is a way of switching back on (or turning up) responses that the virus has managed to dim.
But TLR2 is also expressed on Treg cells (regulatory T Cells), able to induce immune tolerance (less Th17 inflammation, lower antibody production) to specific immune triggers, so HCV core protein's interaction with Treg TLR2 could be a way of numbing the immune system to the presence of HCV. This can be a good thing in some ways; sometimes "fighting the dragon" aggressively is just too destructive a strategy to be sustainable.

Another way in which HCV is able to reduce the host immune response is by the binding of HCV core protein to the C1q complement receptor; this inhibits complement activation, resulting in depletion of the C3 complement factor, and inhibits proliferation of T cells.

Strikingly, this inhibitory effect of core on lymphocyte proliferation was observed at a concentration of core protein as low as 1.3 nM.

This (I hypothesise) may result in compensatory increase in uptake of, and sensitivity to, LPS, as activation of both TLR4 and the alternate complement pathway by LPS are default ways for the immune system to maintain adequate activity (uptake of LPS from the intestine is not normally an accident, but a regulated and pseudo-hormonal activity). Thus restoring immune activation through TLR2 may decrease the LPS sensitivity which drives liver inflammation, as well as improving immune surveillance of and response to the ongoing HCV infection. As well as spirulina, probiotic bacteria such as Lactobacillus Rhamnosus also have TLR2 activity (PDF).

My own suggestion would be to combine live Rhamnosus and/or Del-immune V with sprirulina or chlorella. The quantity of chlorella consumed in that paper seems rather daunting, and spirulina is a rich source of iron, so it will be good if lower intakes are effective. My own experience is that spirulina and probiotics go well together. Spirulina is also a very good source of mixed carotenoids, and high carotenoid intakes are (independently of retinol) associated with lower rates of hepatocellular cancer in chronic hep C populations; it is also a source of vitamin K2. (It is important to buy algal products from reputable suppliers who will test them for hepatotoxic contaminants).

Fatty liver, or steatosis, is a metabolic phenomenon and mainly diet driven and is a virtual precondition for hepatic fibrosis. Fibrosis itself, on the other hand, seems to be an immunological phenomenon, with the aspects of diet that have most influence being concerned with the microbiota (probiotics, prebiotics, parasites, pathogens, spices, and active foods like algae), the movement of LPS into the liver (polyunsaturated vs saturated fats), and the immune response to these (vitamins A and D, niacinamide and herbal medicines), as well as glucose and insulin regulation.

(Note: in this neural stem cell paper http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010496 "the diet supplemented with spirulina was able to negate ...an acute systemic inflammatory insult of lipopolysaccharide")

(More Music: Sketches of Spain by Miles Davis)

Maybe Trans Fats are Not the Devil

Trans-palmitoleic acid isn't a special trans-fat like CLA (which everyone agrees is good). It's found in both dairy fat and partially hydrogenated vegetable oil. So why do people with the highest levels of TPA have a halved risk of developing diabetes?

2013 Apr;97(4):854-61. doi: 10.3945/ajcn.112.045468. Epub 2013 Feb 13.

trans-Palmitoleic acid, other dairy fat biomarkers, and incident diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).

Mozaffarian D, de Oliveira Otto MC, Lemaitre RN, Fretts AM, Hotamisligil G, Tsai MY, Siscovick DS, Nettleton JA.

Source

Division of Cardiovascular Medicine and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, Harvard School of Public Health, Boston, MA.

Abstract

BACKGROUND:

Dairy consumption is linked to a lower risk of type 2 diabetes, but constituents responsible for this relation are not established. Emerging evidence suggests that trans-palmitoleate (trans 16:1n-7), a fatty acid in dairy and also partially hydrogenated oils, may be associated with a more favorable metabolic profile and less incident diabetes.

OBJECTIVE:

We investigated the association of trans-palmitoleate with metabolic risk and incident diabetes in a multiethnic US cohort.

DESIGN:

Phospholipid fatty acids and metabolic risk factors were measured in 2000-2002 among 2617 adults in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of white, black, Hispanic, and Chinese Americans. In 2281 participants free of baseline diabetes, we also prospectively assessed the risk of new-onset diabetes (205 cases) from baseline to 2005-2007.

RESULTS:

trans-Palmitoleate concentrations correlated positively with self-reported consumption of whole-fat dairy, butter, margarine, and baked desserts and with other circulating biomarkers of both dairy fat and partially hydrogenated oil consumption, which suggested mixed dietary sources. After multivariable adjustment, trans-palmitoleate concentrations were associated with higher LDL cholesterol (quintile 5 compared with quintile 1: +6.4%; P-trend = 0.005), lower triglycerides (-19.1%; P-trend < 0.001), lower fasting insulin (-9.1%; P-trend = 0.002), and lower systolic blood pressure (-2.4 mm Hg; P-trend = 0.01). In prospective analyses, trans-palmitoleate was independently associated with lower incident diabetes (P-trend = 0.02), including a 48% lower risk in quintile 5 compared with quintile 1 (HR: 0.52; 95% CI: 0.32, 0.85). All findings were similar between men and women and between different race-ethnic subgroups.

CONCLUSIONS:

Circulating trans-palmitoleate is associated with higher LDL cholesterol but also with lower triglycerides, fasting insulin, blood pressure, and incident diabetes in a multiethnic US cohort. Our findings support the need for further experimental and dietary intervention studies that target circulating trans-palmitoleate. The MESA trial was registered at clinicaltrials.gov as NCT000054

Trans-palmitoleate was associated with substantially lower incidence of diabetes, with multivariable-hazard-ratios=0.41 (95%CI=0.27–0.64) and 0.38 (95%CI=0.24–0.62) in quintile-4 and quintile-5, versus quintile-1.

One might surmise that in this case either the health benefits of increased fat intake override any negatives from hydrogenated vegetable oils (backed up by the finding that palmitoleate from DNL is associated with negative effects that are the inverse of those associated with trans-palmitoleate), or the health benefits of dairy fat are so profound that the negative effects of hydrogenated oils are swallowed up by them.

P.S. A few thoughts on the MESA trans-palmitoleate and palmitoleate studies.
I've looked at some of the other MESA research (there is a great deal of it) and this group's epidemiological work stands out for these reasons:
1) They are measuring an accurately quantifiable factor that is diet-dependent, not relying on food frequency questionaires.
2) They have verified that that factor does correlate with reported dietary intake
3) They are using an actual disease diagnosis (DM2) as the end-point, as well as differences in serum markers.
4) These are prospective studies.
5) Given the short follow-up period (5 years) the odds ratios for DM2 incidence are striking.
6) There is little in the way of a priori assumptions to colour the interpretation of the data.

I was going to give the whole algae as immune stimulants theme a rest, until Silvia Hinojosa-Price sent me this paper.
Spirulina Platensis versus Silymarin in the treatment of chronic hepatitis C virus infection. A pilot randomized, comparative clinical trial.

I've been reading these Hep C natural therapy papers for many years now and this is the first to record SVR. Essentially, this means that the treatment (Spirulina, a simple dried extract at 500mg 3x daily) was associated with undetectable virus levels after 6 months treatment. Only in 13.3% of the subjects (4 of 30, with another 2, or 6.7% having a significant drop of over 2 log) but still - this NEVER happens in clinical trials of "natural" or "alternative" therapies. The best will often lower viral load, but not to undetectable levels. HCV researchers never use the word "cure", but having no virus is as close as it gets. There are a few caveats I'll add later, but this is an impressive paper. I don't often see papers of this sort so well written or with the data so well presented. There's not much left to the imagination, which is how it should be. The authors are coming from a conventional, standard of care background and have had their interest piqued by patients reporting beneficial effects from Spirulina supplements; so they ran this clinical trial.
The motivation to conduct this study, "apart from the theoretically convincing background", was the unintended data coming from some of our patients who took Spirulina as nutritional supplement and reported to us marked improvement of the general well being and sexual activity. From this probing experience, as well as from the results of Danoff A, et al. [44] and Soykan A, et al. [45] who reported an association of chronic HCV with depressed sexual functions independent of depression, we opted to compare the effect of both treatments on sexual functions beside the other efficacy parameters in such patients. We assumed that improvement in sexual appetite; frequency and performance are logical indicators for the improvement in the overall wellbeing. Our results went in agreement with this assumption.
This is how it should be done, respecting the patients' anecdote as a hypothesis generator, yet these kinds of trials often end in disappointment. But not this time. Yakoot and Salem were smart enough to allow the trial to last 6 months. They made the logical assumption that the time needed for any response to Spirulina would be at least as long as that needed for a response to Interferon-based therapies.
We hypothesized that there must be a time needed to establish and solidify the immune mechanisms behind the activation, release and action of endogenous interferons and other interplaying cells and mediators. Even the parenterally administered high dose of interferon alpha took some months to manifest its maximal virological response, that is why we wait at least 3 months to predict the sustained virological response through the early complete or even partial virological response.

Silymarin was used as an "active placebo". In other words, Spirulina was compared to extract of Milk Thistle seeds (140mg 3x daily), the supplement most likely to be used by chronic Hep C sufferers, but one that has only a small objectively measurable effect (at least, in this basic dosage form: but you can see here that other, more bioavailable forms might be worth testing).
Lo and behold, one of the Silymarin group (1 of 29) had an SVR. This reduced the significance of the 4 Spirulina SVRs and doesn't seem to be commented on. For what it's worth, Silymarin does have inhibitory effects on HCV replication, but these should be mild at the levels attained in a 140mg 3x daily dosing, and it's the first I've ever heard of SVR from Silymarin. However, there is a natural rate of spontaneous clearance in chronic Hep C, estimated at 1% per year, though no-one really knows and most clinicians would rather not follow up such cases. Lazarus was a disappointment to his doctor.
The patients with the lowest viral loads were the most likely to have an SVR in response to Spirulina. In those patients with viral loads below 100,000 the difference between Spirulina and Silymarin was statistically significant.
Our results showed significantly greater effects of Spirulina than Silymarin on most studied parameters including the significantly greater reduction of serum ALT and the greater improvement in both disease specific health related quality of life and sexual functions scores. Though the virological response rates were not statistically significantly different between the 2 treatment groups, yet it reached the level of significance with the one sided Z test for proportions in those who presented with low or intermediate baseline viremia.

One limitation was the absence of post-treatment follow-up.
It is the main limitation of our study that we did not follow up patients for one year treatment followed by 6 months off-treatment period as the case in the protocols for the study of interferon alpha based therapy. We designed this relatively short term pilot study to answer a simple research question; is there any therapeutically feasible potential for Spirulina in chronic HCV patients, worthy to conduct a larger study with longer follow up period.
I would expect that some of the SVR cases would relapse once they stopped taking Spirulina; after all, this happens with conventional drugs. But why should anyone stop taking Spirulina? It would be no imposition at all to keep taking it for the rest of one's life, indeed it probably be a good idea even if the sustained viral response didn't depend on it.
This study was mainly focusing to help a considerable percentage of chronic HCV patients who are facing the situation of contraindication, intolerability or non-response to the current gold standard therapy. They usually become feeling hopeless and unsecure with deterioration in their overall wellbeing, functional status and quality of life. If further studies confirm our results with reproducibility, this could be an alternative treatment in such situations if at least it can improve quality of life, physical activity and performance. We did not focus on the luxury of sustained virological response at this exploratory stage, but it will be our objective in the coming planned study.

Where to from here?
The raised issues from the already discussed in-vitro and preclinical data about the potential immune stimulation and virus entry blocking also urged us to plan to test a new hypothesis; could the complementary therapy with Spirulina improve the response to the current gold standard antiviral therapy?. This will be tried to answer in our next study; through testing the effect of combining Spirulina with the current gold standard therapy, or the effect of offering a lead-in course for those who have high baseline virus load.

I would like to see a longer study of constant treatment, similar to the long-running Japanese zinc carnosinate (Polaprezinc) study. And there is no reason why the dose couldn't be increased. The nutrients that support Interferon - B12, D3 and retinol - could be optimized. And so on.

About the Physician Authors; AA Salem has authored 420 medical papers including 5 based on clinical experience of HCV cases. M Yakoot has authored 13 papers, mostly clinical trials of dietary supplements or reviews of OTC drugs.

The competing interests:
Beovita-Safe Pharma, a Joint German Egyptian Company, Katzbachstr. 29, D-10965 Berlin, had supplied the drugs and partly the costs of the laboratory tests.

There seems to be nothing unique or patentable about Beovita-Safe Pharma's Spirulina or Silymarin products that would prevent the results being replicated with another company's products. I suspect Beovita-Safe Pharma's motivation was to have the use of their products accepted as safe and justified by the clinicians treating their customers. I wonder what Beovita-Safe Pharma will do with this additional information. They'll certainly be motivated to support other trials.
We opted to use the whole herbal extract and not any one of the fractionated bioactive molecules presuming that the whole natural multi-components as previously discussed in introduction could offer not only antiviral activity but also other immune enhancing activities that might be summated together to produce therapeutic effects on this state of chronic viral infection that evades the immune system.

Update: I looked at Spirulina products while shopping today. Most are whole dried Spirulina 500mg tablets, but I found one product that was a "herbal extract" of 2,300mg Spirulina in an approximately 500mg cap (I suspect) together with 50mcg selenium from selenomethionine. It had been made in New Zealand for the Japanese market.
This may be close to the Beovita product. I hope to find out more - including, what is the iron content of the Beovita tabs? 1g of Spirulina can supply 3mg iron and a standard dose of whole dried spirulina is 9g daily.

I haven't had my Diet Wars writing published before, unless you count my many letters to the editors of The Herald, Listener, and Otago Daily Times, letters which, I'm pleased to say, do often get published.
This is the first hard copy of an article that wasn't just a response to some piece of stupidity in the press.

It was commissioned for inclusion in the first edition of the free Café Reader. This will hopefully be available in every café in New Zealand. Apart from my polemic, it also contains writing from the finest local talent. I opened it at random (after checking my piece for typos, phew!) and Simon Sweetman's party piece is the funniest thing I've read in ages. Put together by Phantom Billstickers, thanks to Jim and Kelly Wilson and no doubt other committed team members that I haven't had dealings with.

And there we have it. I will reprint the whole article in a few weeks for overseas readers.

Meanwhile, some exciting science news; expert scienticians have finally invented a high-fat diet diet that DOESN'T produce fatty liver in Wistar rats, even with prodigious overfeeding!

Long term highly saturated fat diet does not induce NASH in Wistar rats

Background

Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats.

Methods

21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH.

Results

MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25–28% vs standard).

Conclusion

Long term high saturated fat feeding led to increased "peripheral" fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH.

The full text paper is here.

The letter to the editor is a miniature literary form like the haiku, and one more transient than the blog post. I have written a great many over the years; no-one taught me, I believe that no university or technical college teaches the art that I have acquired "by doing".
When you write to the editor you are constrained in time; your letter must be promptly relevant to a published letter or article. You are constrained in subject; you must rehearse the points raised and your own must be relevant to them. You are constrained in space to a paragraph or so, and you are equally constrained in style. Admittedly a smaller newspaper which I read in Tauranga has taken to publishing text messages with all their barbarous orthography intact, but a letter to an august organ such as the New Zealand Herald, with a circulation of over 500,000, must be a regular English prose composition (though if you can't quite manage that but still have something to say, the sub-editor may be generous with their aid).
Grandstanding, quirkiness, abuse, bare-faced flouting of logic, use of the word teh, substituting $ for S, multiplication of the letter K, obscenities, gratuitous offensiveness, and all the other tools of the blogger's trade will not be countenanced by the ladies and gentlemen of the press.
My recently published letter was in response to one on the subject "Tackling Obesity" by one Peter Davis. It was reasonable enough and noted as I have done the sad decline in our once-great nation's health. The writer wondered if our armed forces might one day run out of healthy recruits. My first impulse was to respond that, obesity epidemic or not, the New Zealand defense forces will always be able to find the 18 or so recruits they need each year from a population of 4,405,200 at last count. However, I decided to drop the cheap joke to focus on a better target, a reference to eating too much and not exercising enough as causes of obesity. Really one can build a great deal around a light slap at this notion.
This is my letter as it was published on Monday, May 13th:

Peter Davis is right to insist that the social and health costs of the obesity epidemic require action.

Any measures taken should first increase research, while in the interim promoting the most successful overseas interventions, at present low-carb and ancestral diets, and developing them to suit New Zealand's needs.

It is presumptuous to say that obese people have eaten more and exercised less than others. First, such behaviour does not always result in obesity. Secondly, if I weighed an extra 45kg I would automatically be exercising a great deal harder than I do today just to go about my life, and this would probably require extra nutrition.
Perhaps it is the declining quality of food - particularly the substituting of cheap starches, sugars and oils for nourishing fare - which is more than anything responsible for the declining quality of health in this area.

Yours Faithfully,

George Henderson

And this is the letter as I sent it. I am including this version so you can appreciate how lovingly the sub-editor refined and polished my points, erased my mistakes, and improved upon my style, still slightly imperfect after all these years.

Dear sir/ma'am,

Peter Davis is right to insist that the social and health costs of the obesity epidemic require action. To avoid making things worse any measures taken should first increase research, while in the interim promoting the most successful overseas interventions, at present low-carb and ancestral diets, and developing them to suit New Zealand's needs. It is presumptive to say that obese people have eaten more and exercised less than others. Firstly, such behaviour did not, and does not, always result in obesity. Secondly, if I weighed an extra 100 pounds I would automatically be exercising a great deal harder than I do today just to go abut my life, and this would probably require extra nutrition, especially if the food available was of poor nutritive quality.
Perhaps it is the declining quality of food, i.e. the substituting of cheap starches, sugars and oils for nourishing fare, that is more than anything responsible for the declining quality of New Zealanders' health in this area.

Yours Faithfully,

George Henderson

Notice that, as New Zealand went decimal in 1967, a fact I had forgotten due to my excessive reading of U.S. diet books and blogs, my reference to a round 100 pounds was converted to a rather clunky 45 kilos.

What I believe distinguishes this letter from my earlier published efforts is the sheer number of concepts I was able to address. Unintended consequences ended up on the cutting room floor, but I was able to retain

- scientific research as the proper basis for policy decisions

- the paramount effectiveness of low-carb and paleo (without claiming that current options are perfect)

- a subtle reference to "The Native Diet"* T.V. program and other local initiatives

- a Taubesian dig at CICO

- a reference to empty calories (food quality)

- a swipe at the 3 Paleo devils, grains, sugars and oils, ignoring the expected whipping boy, my buddy fat.

And really, that's enough to be going home with.

* "The Native Diet is a concept derived from traditional Māori eating, activity and the 1920′s research of Dr Weston Price, who after visiting 14 indigenous nations including Māori, concluded the western world must look back at the traditional diets of these people groups for the future health of the next generation. Price advocated prohibiting processed foods from diets of Americans, something that has not been followed up."

Aspirin (acetylsalicyclic acid) is one of those drugs that blurs the distinction between the natural world and the products of human ingenuity, being a barely-tweaked analogue of salicylic acid. Salicylic acid is not only prevalent in the diet, it appears to be synthesised endogenously in fasting states.
(music: Seven Fishes by Jigsaw)

Aspirin has long been regarded ambivalently in medicine. On the one hand it kills pain and reduces fever, on the other hand excess can make the gut bleed and damage the kidneys, and even cause hepatitis. Low-dose, buffered aspirin is commonly used as a preventive of heart attacks and strokes, but its overall effectiveness in this role is questioned:

Meta-Analysis of Multiple Primary Prevention Trials of Cardiovascular Events Using Aspirin

The meta-analysis suggested superiority of aspirin for total CV events and nonfatal MI, with nonsignificant results for decreased risk for stroke, CV mortality, and all-cause mortality. There was no evidence of a statistical bias. In conclusion, aspirin decreased the risk for CV events and nonfatal MI in this large sample. Thus, primary prevention with aspirin decreased the risk for total CV events and nonfatal MI, but there were no significant differences in the incidences of stroke, CV mortality, all-cause mortality and total coronary heart disease.

So the findings in this survey were unexpected:

Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.

Methods We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health–AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.

Results Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.

Conclusions Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.

Now, these are huge correlations, especially when you consider that the use of NSAIDs is considered to put one at risk of leaky gut syndromes, and that SIBO and endotoxaemia are proving to be significant factors in the development of chronic liver disease. When epidemiology goes so strongly against the grain of one's expectations, one really should sit up and take notice. There's an extra convincing feature here - the differential correlations of aspirin (less CLD, less HCC) and other NSAIDs (less CLD but no reduction in cancers). If the result was co-incidental (people with better liver function more able to use NSAIDs, for instance) this difference shouldn't exist. Non-aspirin NSAIDs lumped together by the methodology include (are mainly) ibuprofen and paracetamol (acetaminophen) and the latter can cause liver damage by depleting reduced glutathione. This has cancelled out the anti-cancer benefit (we might hypothesise) but the aspirin-like anti-inflammatory effects of ibuprofen still show.

Of course if you already have low platelets and poor blood clotting due to cirrhosis it might be a bit late to take any advantage you might see in this research. However, there is an alternative theory; that Aspirin should be considered as a salicylate supplement, and that fruits and vegetables, which are naturally rich in salicylate, can supply the same benefit. Wiki lists the sources thus:
Unripe fruits and vegetables are natural sources of salicylic acid, particularly blackberries, blueberries, cantaloupes, dates, raisins, kiwi fruits, guavas, apricots, green pepper, olives, tomatoes, radish and chicory; also mushrooms. Some herbs and spices contain quite high amounts, although meat, poultry, fish, eggs and dairy products all have little to no salicylates. Of the legumes, seeds, nuts, and cereals, only almonds, water chestnuts and peanuts have significant amounts.

Almonds just got interesting again...

Some people are intolerant of salicylates. These people may have little need for aspirin anyway if blood salicylate levels are naturally high. Removing 75% of salicylate from the body involves conjugation with glycine (requiring pantothenic acid - vitamin B5 - plus sulfur, as acetyl CoA), and clearance of salicylate might improve on a paleo diet with bone broth to supply glycine, and low carbohydrate intakes to stimulate trans-sulfation and acetyl-CoA synthesis.

Anyway the take home message from the Aspirin study as I see it - if you're concerned about the health of your liver, and your platelets are still in the normal range, you needn't be afraid to use aspirin. Though it might be a good idea to also ensure you're getting enough vitamin K.

Ginkgo Biloba Extract and Cancer

It's a common enough fallacy that natural medicines, especially ones in common use, can't be as harmful as pharmaceuticals. The appeal to nature, the appeal to antiquity, and all that. The fact is that the supplement industry is very poorly regulated in most countries, and no-one has yet worked out how to regulate it in a way that consumers, long used to experimenting freely with often cheap and sometimes effective natural medicines, will tolerate. It doesn't help that regulation is usually the business of government agencies that are seen, with some reason, as being in the pocket of Big Pharma. A few weeks ago Stephan Guyenet tweeted about this study (PDF) which shows commercial ginkgo extract is highly carcinogenic in rats and mice.

Liver: The incidences of multiple hepatocellular

adenoma, hepatocellular carcinoma, and hepatoblastoma

were increased in all dosed groups of males; multiple

hepatocellular adenoma incidences were increased in all

dosed groups of females, and multiple hepatocellular

carcinoma and hepatoblastoma incidences were

increased in 600 and 2,000 mg/kg females. When single and multiple neoplasm

incidences were combined, significant increases were

seen in the incidences of hepatocellular adenoma in

200 mg/kg males and all dosed groups of females,

hepatocellular carcinoma in all dosed groups of males

and 2,000 mg/kg females, and hepatoblastoma in all

dosed groups of males and 600 and 2,000 mg/kg

females. These significantly

increased incidences also exceeded the historical control

ranges for these neoplasms from corn oil gavage studies

and all routes of administration (except for hepatocellular adenoma in 200 mg/kg females)

(Cancers were also found to be significantly increased at a number of other sites including the nose and thyroid).

One could take this with a grain of salt, rats being rats, and the doses being a little higher than human doses, but the paper does refer to human trials, and these results too give cause for concern.

Humans

Two epidemiological studies explored carcinogenicity

associated with use of Ginkgo biloba supplements. In a

population-based, case-control study reported by Ye

et al. (2007), in which the case group included 668

women in Massachusetts and New Hampshire

diagnosed with epithelial ovarian cancer matched to

721 women in the control group, an inverse association

(OR=0.41; 95% confidence interval, 0.20-0.84; P=0.01)

was found between Ginkgo biloba use and risk for

ovarian cancer. A more recent study by Biggs et al.

(2010) used data from the largest epidemiological study

of Ginkgo biloba efficacy (Ginkgo Evaluation of

Memory Study) conducted to date to analyze cancer as a

secondary endpoint. The study population consisted of

3,069 participants, age 75 years or greater, that were

randomly assigned to receive twice daily doses of either

a placebo or Ginkgo biloba extract (120 mg EGb 761®)

and were followed for approximately 6 years.

Researchers found an increased risk of breast (hazard

ratio, 2.15; 95% confidence interval, 0.97-4.80; P=0.06)

and colorectal (hazard ratio, 1.62; 95% confidence

interval, 0.92-2.87; P=0.10) cancers and a decreased

risk of prostate cancer (hazard ratio, 0.71;

95% confidence interval, 0.43-1.17; P=0.18) in the

population receiving Ginkgo biloba extract.

It seems to me that a more than doubled incidence of breast cancer in a randomized controlled study is the kind of result that should have been more widely discussed than it was. If this happened in a study of statins or aspartame, the whole internet would be abuzz with it. Why does Ginkgo get a pass?

Ginkgo Biloba leaf extract is not a traditional Chinese medicine. There is some mention of monks at some time making tea of the leaves, but they do not appear in any TCM formulary that I have perused. The seeds appear occasionally but are recognized as toxic and their use is rare. Ginkgo leaf extract contains many worthwhile compounds (I could fill another post with these), and it's the best treatment I know to give someone who has memory impairment from chronic marijuana use. It has a potent antifibrotic effect and has been used in modern Chinese hepatitis therapies. It will inhibit many cancers in vitro (the difference can be small between what might cause cancers, and what might treat them; some chemo drugs, as well as radiation, are carcinogenic). I used to take Ginkgo regularly every now and then. I'll still take it when I have to drive long distances, on the principle that the increased alertness will reduce risk in the short term without exposing me to longer term risk.
Ginkgo is a mixture of many different types of phytochemical, and some might be more effective once isolated. It seems likely that the carcinogenic component will be identified and removed from extracts, hopefully sooner than later. The uncritical acceptance of the idea that whole herbal extracts are intrinsically more effective and safer than isolated compounds may have been mistaken in the case of Ginkgo.

Well, here we have a drug that might be better for us than was previously thought, and a popular herbal product that might actually be harmful in its present form.

What is the world coming to?

Zinc supplementation therapy improves the outcome of patients with chronic hepatitis C (2012)

Results

Four of 5 posttreatment liver biopsies showed histologic improvements in steatosis (P=.02) inflammatory grade (P=.02), and fibrosis (P=.07). Six months of a low-carbohydrate, ketogenic diet led to significant weight loss and histologic improvement of fatty liver disease.

Last but not least, some case studies from everyone’s favourite blogger, Stephan Guyenet at Whole Health Source. Stephan is someone who has taken into account choline and all the other factors I’ve mentioned. Fatty Liver Reversal

Cataracts and Vitamins: The Real Story

Is this research?

Is it reliable?

Is it scientifically plausible?

So, in real life?

References:

Vitamin C lowers cataract risk:

Vitamin E lowers cataract risk:

Smoking increases risk:

Healthy diet prevents cataracts:

Efficacy and safety of high-dose vitamin C on complex regional pain syndrome in extremity trauma and surgery--systematic review and meta-analysis.

Source

Abstract

Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages.

Source

Abstract

Source

Abstract

trans-Palmitoleic acid, other dairy fat biomarkers, and incident diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).

Source

Abstract

BACKGROUND:

OBJECTIVE:

DESIGN:

RESULTS:

CONCLUSIONS:

Long term highly saturated fat diet does not induce NASH in Wistar rats

Background

Methods

Results

Conclusion

Meta-Analysis of Multiple Primary Prevention Trials of Cardiovascular Events Using Aspirin

Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma

Last but not least, some case studies from everyone’s favourite blogger, Stephan Guyenet at Whole Health Source. Stephan is someone who has taken into account choline and all the other factors I’ve mentioned.

Fatty Liver Reversal