L-Valine, Zinc supplementation, the Fructose Lipid Hypothesis, and the n=1 Updated

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 (and it will presumably run unevenly or at a reduced rate if this intake/exhaust system is out of balance). 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 propionate supplied by 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 (note that the l-valine, as far as I know, could be metabolized elsewhere, e.g. muscle, but.the propionate finds its way to the hepatic mitochondria). 

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? Is l-valine synergistic with alpha-lipoic acid in this scenario (which would tend to confirm the succinyl-CoA mechanism)? 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. (updated: another baddish day today. Water gave some relief eventually - I didn't expect it to work like an inefficient drug. Can disease states tend back to homeostasis - is that why drugs often stop working eventually? Next time I write about this I hope to be able to assess it properly)

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.

What would Bluebelle Eat? Feeding the Paleo Dog.

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 [edit] 2-3 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 (edit - grapes and raisins are toxic to dogs, don't feed these) 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.

Rich Van Konynenburg R.I.P. - Methylation and Glutathione.

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. 

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:
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." 

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. 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

Fish Oil, Krill Oil, and Hepatitis C

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

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

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

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

For one thing, they all inhibit HCV replication.

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

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

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

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

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

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

(click on "look inside" link).

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

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

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

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

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

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

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

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

Anyhoo; what to recommend?

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

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

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

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

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

My Dietary Recommendations for Liver Health

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

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

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

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

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

or are suspected, to prevent it.

In general terms

1) Protein is very protective of the liver,

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

sugars can be harmful, and

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

There are 3 specific substances to minimize or avoid:

Minimize:

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

juice, honey, as well as sweet fruit).

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

insulin response to glucose; high consumption of fructose can cause

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

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

fructose for most people.

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

promotes VLDL expression, increasing the release of virus to the

bloodstream).

Minimize:

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

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

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

occasional nuts and seeds. Vegetable oils contain large quantities of

omega-6 lineolic acid, which promotes inflammation and suppresses

omega-3 fats.

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

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

When large amounts of polyunsaturated fats are added to alcohol or

drugs, liver damage and fibrosis are increased.

Persons with Hepatitis C show increased fibrosis and worse responses

to treatment with higher PUFA content of the diet.

Vegetable oils decrease LDL and HDL cholesterol, while saturated

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

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

response to treatment.

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

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

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

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

cocoa, and coconut is protective.

Minimize, and if possible Avoid:

Gluten grains.

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

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

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

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

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

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

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

contains added iron.

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

which allows bacteria and toxic undigested proteins to enter the

bloodstream from the gut.

Parts of these bacteria called LPS can trigger inflammation in the

Liver.

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

gluten sensitivity disease. Coeliac and non-celiac gluten sensitivity

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

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

with Hepatitis C.

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

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

so many digestive challenges.

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

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

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

starches, and green vegetables are richer in protective

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

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

tolerate other gluten grains can tolerate oats in small amounts.

Some special foods that protect the liver:

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

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

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

cirrhosis. Red meats are best.

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

protective against fibrosis.

Coffee consumption protects against fibrosis and cirrhosis from

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

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

tea.

DHA from oily fish is protective against fibrosis in moderate

supplement doses but may increase it in excessive amounts.

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

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

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

Beetroot contains betaine and some unusual and potent antioxidants,

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

15 minutes, roast for under 1 hour).

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

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

fermented soy.

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

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

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

Carotenoids, folic acid, and flavonoids protect against fibrosis and

are found in green leafy vegetables; sulfur compounds found in

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

immunity and protect against cancers.

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

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

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

and coeliac disease.

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

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

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

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

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

vegetables and berries are excellent foods. Prunes and raisins are

good dried fruits.

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

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

best varieties.

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

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

lack.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

rather than deep-frying.

Some references:

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

Alcohol and dietary intake in the development of chronic pancreatitis

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

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

search function)

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

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

Relationship between Dietary Beef, Fat, and Pork and Alcoholic

Cirrhosis; Bridges

Dangerous Grains; book by Hogan and Braley.

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

advice on supplements and drugs)

Applying principles of HCV virology to the Development of new

Antiviral Therapies; Stephen J. Polyak

(c) George D Henderson 2012


Feel free to use this.

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