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Tuesday, 13 November 2012

HCV replication; diabetes, main roads, railways, and tanks.

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.
DGAT1 - 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 DGAT1 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:

 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).

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: )

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."
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:

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." 

Tuesday, 6 November 2012

Eat shit and live! The hygiene hypothesis n=1

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.
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.

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