Saturated fat IS good for you, but how much polyunsaturated fat do you need?

Working on the "Real Food" AUT dietary guidelines submission it became clear that neither the epidemiology of the lipid hypothesis nor the RCT experiments testing it were designed to separate the supposed artery-clogging effect of saturated fat from the purported heart-healthy effect of polyunsaturated fat.
What we had was a series of comparisons of higher SFA and lower PUFA vs. lower SFA and higher PUFA. There were no investigations of either higher SFA in a diet with optimal PUFA, or of deficient PUFA in a diet also low in SFA.
The former of these, higher SFA in a diet with optimal PUFA, is what the low-carbohydrate, high-fat (LCHF) diet supplies. The latter is a danger on a low-fat diet, so "let them eat margarine".

1946 Dietary Guidelines - not bad at all.

Richard Lehman described the mindset in a recent BMJ blog: 
If I despair of meta-analyses, what can I say about dietary surveys? Actually, they’re quite fascinating, though they rarely bear any definable relation to human health. Diet and religion are often closely aligned. The authors of this paper have got religion bad: “Diet is one of the fundamental risk factors for health, disease, and disability in the world. Indeed, given that trends in metabolic risk factors such as blood pressure, cholesterol, glucose, and body mass index are being largely driven by nutrition, suboptimal diet is the single leading modifiable cause of poor health in the world, exceeding the burdens due to tobacco and excess alcohol consumption combined.” They then go on to look at fat. Why, I know not. But it is quite interesting to see which countries eat what types of fat. Where people eat more saturated fat, they often eat more unsaturated fat. For all I know this may help to explain why nearly everyone everywhere is enjoying their food more and living longer.
In the paper Richard Lehman is discussing, we find the alarming statement that the Centre for Disease Control (which really should be worrying more about emergent viruses and antibiotic-resistant bacteria and less about fat) thinks that getting 13% of our energy from linoleic acid (omega 6 PUFA) will be "optimal". If that's optimal, what do they consider an excess? This crazy figure is certain to be based on the amount of linoleic acid required to reduce serum LDL to a particular "healthy" target across a Western population, with no thought given to metabolic health, and bearing no relation to any intake humans might have been exposed to for any period in their evolutionary history.

As Peter D. said in a recent comments thread, "You have a basic assumption that blood lipids cause CVD. You will make many wrong choices based on this hypothesis." Now, I don't know what causes CVD. It could be blood lipids - there are intelligent people who think that small, dense LDL particles typical of refined-carbohydrate diets rip up the arterial walls like stilettos on a ballroom floor. But I do know that the assumption that blood lipids cause CVD has led to many wrong choices. Wrong choices in the supermarket. Wrong choices in the design of experiments. Wrong choices in the interpretation of epidemiological data. Imagine what useful drugs statins might be if they were not over-prescribed on the basis of LDL counts, with results like this.

Many analyses of the "lipid hypothesis" epidemiology and RCTs failed to distinguish between omega 6 and omega 3 PUFA, or between vegetable PUFA (linoleic acid and alpha linolenic acid) and long chain polyunsaturated fats found in animal foods like EPA, DPA, DHA and arachadonic acid. This is understandable because, when Ancel Keys cooked up the lipid hypothesis, no-one knew that omega 3 fatty acids existed, let alone that they were essential nutrients. I'm not even sure if anyone realised that omega 6 was essential back then.
We are stuck with an article of faith from the Dark Ages. A diet high in saturated fats that happens to be deficient in polyunsaturated fats - say with fats supplied exclusively from tallow and hydrogenated shortening, with over-cooked boiled meat or deep-fried fish, milk, boiled greens, sugar, and highly refined grains - which was the mid-20th century diet for many in the Westernised world - can be deficient in PUFA. Smoking and drinking and the general lack of antioxidants in the diet, as well as the effect of insulin from the refined carbohydrate, will tend to squander what PUFA there is. Not surprising if this population has more CVD. What will be surprising is, if the saturated fat has anything to do with it. That diet will also be high in monounsaturated fat (beef olein is the MUFA from tallow, used in old-school chip shop fryers), but somehow MUFA gets a pass. It's all very unsatisfactory.


Is there any research that can help us sort out the difference between a lack of PUFA and an excess of SFA? Well, maybe. We can at least see the difference between an excess of PUFA, and a lack of SFA.This study by Amin A. Nanji and Samuel French is an ecological study comparable to Ancel Key's "7 Countries" study, except that it includes 17 countries.
Mortality from cirrhosis in many countries deviates markedly from that expected for a given per capita alcohol intake. We investigated the possibility that dietary factors might explain the deviation expected and actual mortality rates in different countries. Deviations from expected cirrhosis mortality was calculated as a percentage for 17 different countries, all of whom had carrier rates for hepatitis B virus of less than 2%. The percentage of deviation was correlated with dietary intake of saturated fat, polyunsaturated fat, cholesterol, and also with mortality from ischemic heart disease. The percentage of deviation correlated inversely with dietary cholesterol (r= -0.86, p 0.001) and saturated fat (r= -0.80, p 0.001) and positively with polyunsaturated fats (r= -0.55 p 0.05). This suggests that both saturated fat and cholesterol protect against alcoholic cirrhosis while polyunsaturated fats promote cirrhosis. The correlation between percentage of deviation and ischemic heart disease (r= -0.78, p 0.002) suggests that those factors that promote ischemic heart disease protect against alcoholic cirrhosis.


If the factors that promote IHD protect against alcoholic liver disease (ALD), what are they? We can perhaps discard the red herring of cholesterol, which is a marker for animal fat, and which indicates consumption of foods (such as eggs) which are also rich in the essential hepatoprotective nutrient choline. Cholesterol does protect against ALD tested separately, but coconut MCTs (no cholesterol, no PUFA) gives the same protection as tallow (cholesterol, 1% PUFA) when the two are compared.
There has been a large body of animal experimentation designed to elucidate the link between alcoholic liver disease and dietary fats, with occasional testing of acetaminophen (paracetamol) toxicity in the same model. These papers have been analysed expertly by Victoria Prince on her blog and I will not duplicate her efforts.
http://principleintopractice.com/2012/07/23/liver-and-lipids/
http://principleintopractice.com/2012/08/02/liver-saving-saturated-fats/It can quite clearly be seen in Victoria Prince's third liver-and-lipids post below that there are mechanisms whereby saturated fats can have health benefits, distinct from the restriction of PUFA, because saturated fats from coconut and cocoa protect the liver in different ways.
"Thus it seems that dietary MCTs work in a way that maintains the expression of gut tight junction proteins, preventing endotoxin from making it into the circulation, while long chain saturated fats work in a way that increases endotoxin-binding proteins in the liver.  Both prevent endotoxin-induced damage in the liver, but in very different and distinct ways." This is not just relevant to alcoholics and people who consume paracetamol; the fact that long-chain SFAs make the liver less sensitive to LPS is relevant to the studies showing serum markers of dairy fat intake are associated with diabetes protection, because liver inflammation is a precursor to diabetes. And the fact that MCT, made from fats you can only get in significant amounts from coconut or dairy fat, maintains the integrity of the gut, is relevant to the epidemiological studies showing that children who eat margarine and drink low-fat milk have a higher rate of allergies and asthma compared to children who eat butter and drink full-fat milk.
Saturated fats are good for you. Get over it.
http://principleintopractice.com/2013/12/27/chocolate-and-coconut-for-health/


The high fat model of alcoholic liver disease was developed because rats fed normal chow plus alcohol would not develop ALD. The researchers concluded that polyunsaturated fats are "essential for the development of alcoholic liver disease", and that saturated fats are protective.
Diets enriched with saturated fatty acids protect against alcohol-induced liver injury, whereas diets containing polyunsaturated fatty acids promote liver injury (Nanji and French, 1989; Nanji et al., 1989, 1994a). Saturated fatty acids have also been reported to reverse established alcoholic liver injury (Nanji et al., 1995, 1996,1997b).
Now, the fats that promote liver injury are vegetable oils, typically in these tests corn oil and soy oil*. Thanks to the campaign against saturated fats, these are the kind of oils that the fast food eaten by drunken New Zealanders is prepared with today. This seems to be a failure in public health planning.

"You have a basic assumption that blood lipids cause CVD. You will make many wrong choices based on this hypothesis."

(*interestingly fish oil, which has a stronger association with CVD prevention than omega 6, also has a greater promoting effect on alcoholic liver disease, albeit in quantities many times greater than anyone would ever include in their diet. And deficiencies of PUFA, particularly AA, EPA, and DHA, also play a part in ALD, so Samuel French suggsts that alcoholics be advised to replenish these fats by eating "Mediterranean diet" type foods whenever they're in recovery).

The rat model of alcoholic liver disease demonstrates that in this case the effects of high PUFA, while they can be confused with those of low SFA, are not the same. It also demonstrates that the SFA/MUFA ratio of the non-PUFA fat makes little difference (olive oil is almost as protective as beef tallow against acetaminophen liver damage; it seems an oversight that olive oil has not been included in the alcohol experiments, considering how widely it is consumed).
The link between SFA and CVD disappears when SFA is considered separately ("monotonically"), rather than as a marker for PUFA deficiency. The protective association between omega 3 PUFA (the PUFA less likely to be optimal) and CVD remains about the same when these nutrients are considered monotonically, as in the 2013 Singapore Chinese Health study by Koh et al. People who ate more DHA, EPA, and ALA had significantly lower rates of CVD mortality - and they also ate more saturated fat, monounsaturated fat, and omega 6 PUFA, all increasing stepwise with omega 3 across the quartiles as CVD mortality decreased. "Where people eat more saturated fat, they often eat more unsaturated fat. For all I know this may help to explain why nearly everyone everywhere is enjoying their food more and living longer." 
The inverse association between omega 3 and CVD (0.83 OR) is seen with total omega 6 intakes of, on average, 9.9g per day, or 4-5% of energy - almost exactly the same as healthy New Zealanders ate in this paper, and much less than the crazy CDC projection of 13%. All things being equal, the people who eat the most fat, assuming they are not eating solely hydrogenated industrial fats or exclusively low-PUFA fats such as tallow, but are instead getting some fats from wholefoods, including fish, are surely eating enough PUFA to have an optimal intake for CVD prevention, regardless of any effect on blood lipids.

Polyunsaturated fats are essential nutrients, but also highly reactive and bioactive molecules. This means that the association between intake and mortality will follow a fairly steep U-curve, with a "sweet spot" in the middle. Saturated fats are inessential nutrients with low reactivity. The association curve between intake and mortality is likely so flat my dog could skate it.

(not my actual dog)

PUFA, MUFA and SFA occur together in whole foods and in traditional fats and oils. They are not easily separated, even in the laboratory. You can buy pure sugar for a few dollars in the supermarket, it's easily separated from the foods it occurs in, usually to be ladled back into some other food in excessive quantities. You can probably buy purified long-chain saturated fats like palmitic acid from Sigma Aldrich if you have the money and inclination, and MCT is a processed form of medium-chain saturated fat that is sometimes supplemented by ketogenic dieters; I've never seen it, but I've heard it's expensive.
Most people eating a LCHF diet, even those who think "saturated fat is good for you", are not going to go that far. Few are even going to use butter or coconut oil as their only fats, and anyone eating a variety of wholefoods that have been made palatable but not cooked to death is likely to have an optimal PUFA intake, whatever that is.
 

AUT's Submission on Proposed "Changes" to New Zealand's Dietary Guidelines

For the last wee while I've been helping Prof Grant Schofield and his team write a response to the New Zealand dietary guidelines (low fat, high grain, no SFA).
The paper is the PDF linked to in this post.

http://profgrant.com/2014/04/23/the-real-food-guidelines/

The first time I've had my name on a scientific submission, and a fine one it is too, with the collected wisdom of a bunch of scientists from various disciplines, all working together, to a deadline (we had only a few days warning about the new guidelines, and received no background material on the scientific evidence used in their making). I'm proud of what we achieved, see what you think, and spread this document around.

George Henderson

"Everyone should eat what I eat, 'specially cats!"

On Participating in a Phase III Trial of Sofosbuvir and GS-5816 for Hepatitis C

Late last year, after my usual visit to the Hepatology Department at Auckland Hospital (actually it has the encouraging name Liver Transplant Unit, but I choose to ignore that) I received a call asking me if I'd be interested in taking part in a drug trial. I've had Hep C, genotype 3, for a long time, and I've never fancied taking antivirals. When I was first diagnosed in 1991, interferon monotherapy was a terrible thing. Most people who did it suffered greatly, very few cleared the virus (only one guy I know, and he was the only one who didn't suffer at all), and most of those who didn't clear the virus have died of liver cancer since or needed liver transplants. Later on they added Ribavirin to the Interferon, people got a bit sicker but more of them cleared. But still, those who didn't clear weren't better off for having tried. At this point I felt so sick that I couldn't have borne feeling any worse for the 6 months or a year or whatever the treatment took, and the odds didn't seem that good. Later, when I started taking antioxidants, fixing my diet, and feeling much better, I thought "hey, I'm getting things done, feeling good - why risk screwing all that up?". I learned I could control my viral load and keep my liver fat-free by restricting carbs, and that I could get rid of most of the symptoms by eating Paleo, without any longer spending a fortune on supplements.
But over the last year or so I met a few people who'd been in trials of some new drugs. They hadn't needed to take Interferon, they'd cleared the virus, and they couldn't tell me anything bad about the treatment. That sounded promising. I've always thought that "fighting the dragon" was a foolish idea. HCV has some immunosuppressive effects that protect the liver, together with the virus, from the host immune response to some extent. You don't necessarily want to lift that protection without good reason. The virus is still cytotoxic anyway, it's not doing you any favours, but it's mainly the host immune response (often triggered by things like LPS from the gut) that causes cirrhosis. As I put it, "I'm not going to fight the dragon till I see two strong guys holding it down". And it seemed that day might have come. I thought, I'll go into this trial, and if I don't like anything about it, I'll just pull out, wait a bit longer. At best I'll clear the virus, at worst, well, knowledge has its own value to me.
The trial I went into was called VULCAN

Live Long and Prosper

VULCAN is a Phase III trial of Sofosbuvir (NS5B RNA polymerase inhibitor) and GS-5816 (pan-genotypic NS5A inhibitor), with or without ribavirin. Ribavirin might have been a deal-breaker for me - the people who got it suffered fatigue and depression - but I was lucky. I was randomised to receive Sofosbuvir (400mg) and the lowest dose of GS-5816 (25mg instead of 100mg), one pill of each once daily, and the trial was only to last 8 weeks. Would this be long enough? Would the low-dose GS-5816 be enough? Would my low-carb, high-fat diet help or hinder the drugs?
The interesting thing about GS-5816 is, that the viral protein it targets, NS5A, isn't just needed for replication, it's also one of the viral products responsible for HCV interfering with metabolism.

For example:
 The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus RNA genome is shown here to induce the activation of NF-κB and STAT-3 transcription factors from its cytoplasmic residence via oxidative stress. NS5A causes the disturbance of intracellular calcium. Ca2+ signaling triggers the elevation of reactive oxygen species in mitochondria, leading to the translocation of NF-κB and STAT-3 into the nucleus. Evidence is presented for the constitutive activation of STAT-3 by NS5A. In the presence of antioxidants [pyrrolidine dithiocarbamate (PDTC), N-acetyl l-cysteine (NAC)] or Ca2+chelators (EGTA-AM, TMB-8), NS5A-induced activation of NF-κB and STAT-3 was eliminated. These results provide an insight into the mechanism by which NS5A can alter intracellular events relevant to liver pathogenesis associated with the viral infection.
It might be good to have a drug that would intercept those effects, even if it didn't kill the virus. GS-5816 might act as an antioxidant and antiinflammatory in people with active HCV infection. Unlike interferon and ribavirin, this was a drug that might potentially make you feel better, independent of its antiviral effect.

Anyway, I nearly pulled out of the trial when I got my information kit by email. GS-5816 had been tested in humans alright - for 1-9 days in healthy volunteers, and for 3 days in volunteers with HCV..
Here is the email I sent back:

after careful consideration I have decided not to take part in this trial. However I still want to be considered for future trials.
My reasons, in the event they may be useful to know, are as follows:
1) Efficacy. I understand from my reading that combinations including sofosbuvir have already proved effective in Gt1. It is reasonable to expect that they will be similarly effective and safe for Gt3. However this study appears to be trialing a novel combination to see if it is effective.

2) Safety. The novel drug GS-5816 has, if I read correctly, not been tested for longer than 9 days. 

I have survived with chronic HCV infection since before 1991 and for the last few years have been able to thrive and recover my health. I would like to clear the virus, am prepared to take some risks to do so, including entering a Sofobuvir trial, but I only want to do this once. It appears to me from the studies your group has already published, and from the people I have met who have taken part in them, that there are Sofosbuvir combinations that, combined with my circumstances, would give me an excellent change of clearing HCV safely. It seems inevitable that these will be tested in a Gt3 patient group in the near future, and I would like to be considered for a trial of this description. If not, then I am confident I can manage my condition until the best product makes it to market.
Thank you for including me and for the very interesting reading material.

Well, they rang me up right away and talked me into coming in to see them. The information was out of date; of course people had since taken GS-5816 for long periods, because the trials were up to phase III now. And if anything had gone horribly wrong, Gilead would have cut their losses and moved onto the next drug. And I was impressed by how much the study doctors knew. They were virologists, not hepatologists, and they had worked out how to target the virus without involving the host. The drugs were specific for viral replication products, not for any part of my metabolism or immunity. That was what I wanted to hear.
I knew I wouldn't be allowed to take herbal medicines, but I wasn't prepared for the reason why. Because they might work. Now, herbal meds don't work that well against HCV. But neither do Sofosbuvir or GS-5816, taken on their own. It's only in combination that they deliver a 1-2 sucker punch. So any herb, with its weak effect, could still skew the result when combined with these guys. One or two, like St Johns Wort, could interfere in other ways. I was taking grape seed extract (OPCs) so I stopped that. I had to list whatever else I was taking:

Zinc 30mg as gluconate
Magnesium 150 mg as chelate
B2 25mg
Taurine 1,000mg

I was meant to keep taking these for the next 5 months (8 weeks treatment plus 12 weeks to SVR12) but stopped things I couldn't afford or didn't need any more, like the taurine. I used things like vitamin C and probiotics for short periods when I had a good reason.
They gave me an ECG, multiple blood tests, and sent me off for a fibroscan. The score was 7.4 which is moderately scarred (normal is under 5, cirrhosis is over 12). The blood tests were so hard, what with me having no normal veins left, that I was left out of the pharmacokinetic arm of the study.

My viral load at the pre-trial screening (22-Oct-13) was 600419 (log 5.78) which is fairly high for me, my ALT was 174. With a month to go before the trial started, I decided to get more serious about LCHF. Having a regular series of blood tests due meant I could check out whether going very low carb again would make any difference.
On the day the trial started (18-Nov-13), before the first dose, I gave blood again. Viral load 27167, log 4.43. That's the drop I associate, from previous experience, with being in, or near, ketosis, that is, under 50g carbohydrate/day (previous test was more like 100-150g/day). And, my ALT was 30. That was a big drop, lowest it had been since Hep C diagnosis in 1991. I didn't put that down to ketosis - more likely it was due to the zinc, which I'd started taking about 2 months earlier, based on this paper. It's also possible that stopping the grape seed extract helped. Phytochemicals that are hepatoprotective can sometimes become hepatotoxic. This happens with green tea extract, and I wouldn't rule it out with OPCs, which are chemically similar. Anyway, I started taking the Sofosbuvir and GS-5816.

I went back a week later (25 Nov 2013) - my viral load was  less than 15 (log less than 1.18) meaning it was too small to measure by PCR. And my ALT and AST were 18. And that's the whole story really. My viral load stayed below 15, until the end of the trial (EOT) when it was undetectable (I missed the week 6 test so had no results between week 3 and the EOT. At week 4, which I read at EOT, VL was still detectable at under 15. So I had to wait till week 10, 2 weeks after EOT, to actually find out that I'd cleared the virus, or it became undetectable, sometime between week 4 and week 8).
At week 8, EOT I had another fibroscan. 5.5, down from 7.4. During the course of treatment my scarring had significantly regressed. That is amazing.

Side effects? I had a few, but then again too few to mention. For the first week my skin felt dirty and gritty, and my girlfriend said I was over-sensitive. Maybe true, but I think there was some confirmation bias involved. She hadn't liked me jumping into this experimental drug trial without really consulting her, and I can't say I blame her. I'm sorry I was pigheaded enough to put her through that anxiety. After that, I had a sore throat, cough, a bit of laryngitis, and a swelling under my tongue. And I could taste the drugs all the time. But after week four, nothing at all. The last 4 weeks was a breeze. And, from the start, I was sleeping better, and my energy level was good. There were not serious side effects and I never considered stopping the trial. And I say that as a total hypochondriac who couldn't stand to take aspirin or antibiotics for 8 weeks.

It's week 8 after treatment, so in another month I'll know about SVR12. I have met one person who relapsed after successful treatment on a similar combo, a very unusual outcome so far, but I've had all the advantages they didn't have. But you know, if this didn't work out, I would have no hesitation about trying a longer course, a higher dose, a different combo. It's been no sweat. Amazing. Pharma made something that worked, cured a disease that, as far as I'm concerned, had no cure before.

It can be done.

A Request for Hep C Epidemiologists to Pay More Attention to Linoleic Acid Intakes

Some time ago I came across this interesting paper

Because it seemed to beg the important question of linoleate intake, while addressing both fructose intake and insulin resistance, I took the (for me) relatively unusual step of contacting the corresponding author. I never received a response, but because my email summarised my view of the role of linoleate in chronic Hepatitis C infection (CHC) I have decided to reproduce it here.

Dear Dr Petta,

I am an independent Hepatitis C researcher looking at the relationship between HCV and diet, and I was interested by this paper which you authored.

There is much of interest in the paper and I just want to single out one aspect, typified by this line from a reference paper:
Low cholesterol (OR 0.988, 95%CI 0.975–0.999,P = 0.04) was independently linked to severe fibrosis, and high LDL was the only independent positive predictors of both RVR and SVR (OR 1.036; 95%CI 1.017–1.055; P < 0.001; and OR 1.016; 95%CI 1.001–1.031; P = 0.04 respectively). 
Although these do not seem very large OR differentials (as presented in this example), the finding is often replicated (the ORs will vary depending how "high" and "low" LDL are defined).

Your paper cites one possible mechanism "These aspects have been related, on one hand, to a competition for LDL receptor sites which prevents viral entry into hepatocytes and thus to an increased exposure of HCV to the host serum immune response".

It seems to me that LDL-R numbers, given their role in HCV life cycle, are something that it would be worthwhile for people with CHC to mimimize, and that this is easily possible through diet.

I notice the correlation between fibrosis and fructose consumption, but I feel that if one looked for a correlation between linoleic acid intake and HCV pathology, this would be stronger. I am aware of one study where high polyunsaturated fat intake correlated with steatosis (OR 2.7), while saturated fat was neutral and MUFA was protective. This study did not distinguish between linoleate and other PUFA (ALA, EPA, DHA and arachidonic acid). I believe that if this distinction had been made, linoleate would have shown an even stronger correlation with pathology. 

There are a number of reasons why this should be the case.

Firstly, increased expression of LDL-R increasing viral opportunity to infect HCV-naive cells.

Secondly, steatosis-promoting effect of linoleate. The animal model of NAFLD uses high-linoleate diets and fails to produce steatosis when fats such as butter or coconut oil are fed. NAFLD has become a much more common disease since high-linoleate oils have replaced tallow in deep frying, and linoleate-based spreads have replaced butter.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1805500/

Thirdly, the heating of polyunsaturated oils produces peroxides which directly promote liver inflammation.http://journal-of-hepatology.eu/article/PIIS0168827813002808/abstract

Fourthly, in animal models alcoholic liver disease can only be produced when high-PUFA oils or fats are added to the diet, and it is prevented when beef fat, coconut oil etc are fed concurrently with alcohol.http://download.journals.elsevierhealth.com/pdfs/journals/0016-5085/PII0016508595903542.pdf
Fifthly, linoleate increases both hepatic uptake of cholesterol and its synthesis, and high intakes result in elevations of hepatic free cholesterol and non-esterified fatty acids.

http://www.jlr.org/content/31/8/1413.full.pdf
http://suppversity.blogspot.co.nz/2013/08/high-fish-soy-lard-low-fat-diets-how-do.html

Because EPA, DHA and arachidonic acid all suppress HCV replication and can substitute for dietary linoleic acid in much smaller amounts, it is relatively easy to compose a nutritious diet which is low in linoleate. Many diets today are deliberately designed to minimize this problematic, and currently over-supplied, nutrient, especially diets of the "Paleo" type, such as the "Perfect Health Diet". These diets, which also minimize fructose and high-GI carbohydrates, are often higher in dietary cholesterol than might be considered optimal for someone with CHC, but this could easily be adjusted (or one could supplement with taurine).

My own health has improved since I stopped using rice bran oil and other cooking and salad oils and started cooking with dripping (tallow) and adding butter and olive oil as a seasoning.(*)

I write about these ideas on my blog, discussing a low-carb, paleo approach to Hep C: http://hopefulgeranium.blogspot.co.nz/

In any case, the point of this email is to raise the issue of linoleate from vegetable salad and cooking oils (and also pork and chicken fat) as a worthwhile nutrient to be considered in analysis of CHC and diet, and distinguished from other PUFAs such as omega 3 from plants and fish.

Thanking you,

George D. Henderson  
Huia New Zealand
puddleg@gmail.com      

(* one way in which my health improved after this switch was instructive; being on drugs at the time, I often used to burn myself on the stove, with blisters an inevitable consequence. After increasing saturation of dietary fats, any encounters with hot elements now result instead in patches of dead skin, which quickly clear, and not the classic deep blister.)

Since then, another link between linoleic acid and CHC has turned up; the role of cannabinoid receptors, the natural ligand for which is anandamide (an endogenous cannabinoid derived from omega 6 fatty acids).

The endocannabinoid system (ECS) includes cannabinoid (CB1 and CB2) receptors and their endogenous ligands (i.e., the endocannabinoids anandamide and 2-arachydonylglycerol) as well as proteins involved in endocannabinoids biosynthesis and degradation (1). The ECS is present in the liver and undergoes adaptive changes in response to noxious stimuli. Endocannabinoids as well as CB1 and CB2 receptors (which are, respectively, either faintly or not expressed in normal livers) are up-regulated in experimental liver injury and liver cirrhosis of various etiologies. In vivo, CB1 receptor activation promotes fat accumulation, triggers inflammation in nonalcoholic and alcoholic fatty liver diseases, contributes to the progression of chronic hepatitis to cirrhosis by stimulating fibrogenesis, and is also implicated in hemodynamic and neurological consequences associated with liver cirrhosis, including portal hypertension, encephalopathy, and cardiomyopathy (2–4). Conversely, activation of CB2receptors exerts antifibrogenic and antiinflammatory effects in experimental models of liver disease (5). These pharmacological effects make CB2 agonists and CB1 antagonists promising candidates for the treatment of fibrosis in chronic liver pathologies. By disclosing a prominent CB1-mediated role of anandamide in the early phase of liver regeneration, Mukhopadhyay et al. (6) provide additional and significant support to the prominent role of the ECS in liver biology in an article in PNAS. 

This makes heavy (daily) pot smoking dangerous in presence of liver injury                 

Cannabinoids present in Cannabis sativa (marijuana) exert biological effects via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and CB2 receptors regulate progression of experimental liver fibrosis. We therefore investigated the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C (CHC). Two hundred seventy consecutive untreated patients with CHC of known duration undergoing liver biopsy were studied. Demographic, epidemiological, metabolic, and virological data were recorded, and detailed histories of cannabis, alcohol, and tobacco use over the span of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and activity grades were scored according to Metavir system. Patients were categorized as noncannabis users (52.2%), occasional users (14.8%), or daily users (33.0%), and the relationship between cannabis use and fibrosis progression rate (FPR) or fibrosis stage was assessed. On multivariate analysis, six factors were independently related to a FPR greater than 0.074 (median value of the cohort): daily cannabis use (OR = 3.4 [1.5-7.4]), Metavir activity grade A2 or higher (OR = 5.4 [2.9-10.3]), age at contamination of more than 40 years (OR = 10.5 [3.0-37.1]), genotype 3 (OR = 3.4 [1.5-7.7]), excessive alcohol intake (OR = 2.2 [1.1-4.5]), and steatosis (OR = 2.0 [1.0-4.1]). Daily cannabis use was also an independent predictor of a rapid FPR (>0.15) (OR = 3.6 [1.5-7.5]). Finally, severe fibrosis (≥F3) was also predicted by daily cannabis use (OR = 2.5 [1.1-5.6]; P = .034), independently of Metavir activity grade, excessive alcohol intake, age at liver biopsy, steatosis, and tobacco smoking. In conclusion, daily cannabis smoking is significantly associated with fibrosis progression during CHC. Patients with ongoing CHC should be advised to refrain from regular cannabis use. (Hepatology 2005;.)
Though some studies disagree:Conclusions In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self-medication could explain previous results.

Naturally occuring delta-9 THC is a weak agonist ligand of the cannabinoid receptors, thus can exert both agonist and antagonist effects depending on what other ligands are present. This is why it is non-toxic compared to most synthetic cannabinoids, which are designed as strong agonist ligands.

To cut a long story short, Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity. Or, if one has chronic Hep C, steatosis. As in this paper (the one I mentioned above in the email, with the 2.7 OR between high polyunsaturated fat intake and steatosis - the methodology leaves a lot to be desired, but the the differential between the correlations of the 3 different fat types impresses me).

BTW, CB1 receptor is only strongly expressed, or expressed at all, in injured liver. So it's very unlikely that cannabis causes problems in people without a pre-existing liver condition like Hep C. Synthetic cannabinoids can however cause kidney failure. Which is probably a worse outcome than a little scarring of the liver. 
Nothing demonstrates the lack of legitimacy behind cannabis prohibition as much as the trade in synthetic cannabinoids. But then, consider where sugar sweetened beverages (sodas) came from originally; as "soft drinks", SSBs were developed by temperance advocates as an alternative to hard liquor. The law of unintended consequences is a bitch.

For additional information about linoleic acid's cancer and obesity-promoting effects, this post is a good place to start, and this one has some interesting further data. In fact, there are papers relating to linoleic acid and liver health scattered throughout this blog and I find the search engine pretty useful for recovering them.

Magnus Pyke on energy intake, plus Jack Drummond and Wartime Rationing

Magnus Pyke was the protégé of Jack Drummond, the British nutritionist who largely directed food policy for Britain's war effort during the Second World War. Wiki states:

On 1 February 1940, he was appointed Scientific Adviser to the Ministry of Food. When Lord Woolton became Minister of Food in April 1940, Drummond produced a plan for the distribution of food based on "sound nutritional principles". He recognised that rationing was the perfect opportunity to attack what he called "dietetic ignorance" and that, if successful, he would be able not just to maintain but to improve the nation's health.

Thanks to Drummond's advice, the effect of rationing was to introduce more protein and vitamins to the diet of the poorest in society, while the better off were obliged to cut their consumption of meat, fats, sugar, and eggs. Follow-up studies after the war showed that, despite rationing and the stresses of war, the population's health had improved.

This is misleading; egg consumption was only cut because Britain's eggs (and bacon) were imported from Denmark. And people were encouraged to use meat drippings in place of butter, and use offals in place of meat, both of which were rationed, so it is unlikely fat intake as % of energy fell much (that the well-off were forced to reduce their total calorie intake across the board accounts for the lavish descriptions of meals in the books Evelyn Waugh wrote during the war, Put Out More Flags and Brideshead Revisisted).
An important contribution to the health benefits of rationing was, that the amount of wheat available for consumption by humans decreased, and people were encouraged to eat potatoes instead. More wheat (which was imported from the US and Canada) was fed to cattle for milk production (which was increased), and wheat for bread was milled at a lower extraction rate (less refined) to include more vitamins - a controversial policy as this also decreased its digestibility - and, supplemental B vitamins and calcium were also added to flour, for the first time in the UK. The story is summarised well in a chapter of the book Britain's War Machine.


Jack Drummond was famously murdered with his family in France after the war (a crime which has generated its own conspiracy theory industry among the French), and Magnus Pyke took his place as the don of Nutrition. Success in Nutrition is a 'studybook' (all the information needed to pass all the nutrition examinations of the day) he wrote in 1975, and is as excellent a nutrition text as anyone could wish for. There is a little nod to the lipid hypothesis, but it hasn't skewed the business of getting people properly fed yet - it's a work worthy of Drummond (to whom it is dedicated).
Magnus Pyke O.B.E., Ph.D., C.Chem, F.R.S.C., F.I.Biol., F.I.F.S.T., F.R.S.E. also, incredibly, according to Wiki, wrote the book 'Tricky and Portishead and Other Stonehead Bristol Sounds of the Future'. He makes an appearance (shouting "Science!") in this pop video, so that might even be true.

Anyway, I wanted to quote some words of wisdom from Success in Nutrition, from the chapter on Energy Intake: After warning that BMI does not give an accurate indication of health for everyone, and that variations in BMR render it extremely difficult to specify the right caloric intake for any individual, Professor Pyke concludes;
The most direct way of finding out whether an individual's energy intake is nutritionally adequate is to ask him whether he has enough to eat. If he says 'yes' and if his body weight is satisfactory, his energy intake is satisfactory too.

After discussing (i) different types of bodies, the next section covers
(ii) The influence of social ideas on the ideal body weight.

The purpose of good nutrition is health and health, let us repeat, can be defined as 'complete, physical, mental and social well-being and not merely the absence of ill-health and infirmity'. Different communities have different ideas about what they consider to be the appropriate body weight desirable for complete social well-being.
Although, as we shall explain later, there are certain technical methods for measuring obesity, which is a sign of malnutrition, there is a margin within which people can choose what kind of people they would like to be. A community which thinks a great deal (perhaps in fact too much) about health and nutrition and how its members look, who like their children to be big and their young men and women plump and buxom, may accept certain body weights as standards of optimum nutrition. In another community with a different idea of 'complete social well-being', where people consider that children should work, young men and women overcome strict tests before being accepted as full members of society, and adults think little of their appearance and more of some duty or purpose, considerably lower body weight may be accepted as normal. Yet, though it is difficult for a nutritionist to judge, both may be equally healthy although the members of one community may obtain more units of energy in their diet than those of the other.

- "it is difficult for a nutritionist to judge". Not words we've been hearing much in recent decades, which might be an example of the Dunning-Kruger effect in action.And very interesting that the ideal of a plump, buxom society should be the example chosen as recently as 1975. No-one, however eccentric, would choose that example today. Few nutritionists seem to be aware of the possibility of the existence of a healthy, plump, buxom society; they are more likely to be propagandists for "some duty or purpose", whether it be slimness, the hope of longevity, increased muscular development, or self-sacrificial attempts at saving the planet. In other words, a society's valuing "some duty or purpose" now includes it thinking "a great deal (perhaps in fact too much) about health and nutrition and how its members look".
A good addition to any library of classic nutrition texts, and one that makes me curious to read Pyke's other works, such as Synthetic Food, listed on the Wikipedia page. That book about Tricky and Portishead and the Stonehead Sounds of Bristol doesn't seem to be on Google, unfortunately.

Minimum Pricing of Discretionary Calories as a Potential Government Intervention.

As a general rule, I think it's safe to assume that cheap energy foods are driving the obesity epidemic.
I'm talking about sugar in drinks and lollies, flour in pasta and noodles and bread (one only has to include potatoes, normally a respectable enough vegetable, after deep frying and other extreme processing) and cheap oils. And the mixture of all 3 in biscuits, pastries, cakes, and "treats".

These are the foods the consumption of which has increased during the obesity epidemic. WHO reports that consumption of animal fats has decreased, but total fat consumption has increased. Where intake of calories has increased, these are the foods supplying the extra.

To give only one example, this paper (Behavioral risk factors for obesity during health transition in Vanuatu, South Pacific) found that

"Both the nutrient content and the preparation methods of tinned fish likely contribute to its association with obesity. Tinned fish canned in oil or sauce has higher fat content than most types of fresh fish (21). Furthermore, based on our observations, tinned fish and meat are often served with instant noodles and rice, whereas fresh fish and meat more often accompany dishes made with traditional root crops and vegetables, which are less calorie-dense by comparison. A heavy reliance on tinned fish in urban areas was noted during the first known nutrition survey conducted in Vanuatu in 1951 (22), and has been observed in many areas of the Pacific (23–25).

Our findings are similar to those of the Vanuatu Ministry of Health 1998 NCD survey, which highlighted associations among obesity and daily consumption of nontraditional fat sources (OR=2.19), including oil, margarine/butter, milk, fresh meat, poultry, tinned meat, and tinned fish (11). However, our analyses suggest that tinned fish might contribute more to the risk of nontraditional fats compared to fresh meat (including poultry). In fact, including fresh meat in the nontraditional fats category might actually weaken the observed association, since this emerged as a protective factor in linear regression models, perhaps because fresh meat displaces other less healthy options in the diet."

Tinned fish eaten in the Pacific is canned in soy oil. This, as well as the fact of it being eaten with instant noodles or rice, cancels out the antiobesigenic effects of fish oil omega 3 fatty acids (and, indeed, of protein) in the manner described in this review (Of Mice and Men; Factors abrogating the antiobesity effect of Omega-3 fatty acids).

In the USA, consumption of omega 3 has remained low, but that of omega 6 has climbed

Now it may be that butter is fattening, but this does not mean that it drives obesity (to do this a food has to not only supply energy, it also has to promote fat storage and overeating; there are particular hormonal pathways for this and every fat or carbohydrate or combination of the two doesn't influence these pathways to the same extent or even in the same direction - see the Of Mice and Men paper again - here is where a calorie is not a calorie). But let's assume, for avoiding arguments' sake, evidence to the contrary notwithstanding, that butter and soy oil are equally fattening at 9 calories per gram.
500 grams of butter, in New Zealand costs $4-5.
At $8.49 for 2 litres, soy oil is half that price per calorie.
Extra virgin olive oil, which everyone thinks is healthy, is $11.99 a litre, only a little more expensive than butter. Still cheap for 9,000 calories.
The idea of a minimum price, rather than a tax, is twofold; people might choose to use less fat because the cheapest fats would cost more. But the fats that are nutritious (butter is an important source of fat-soluble vitamins) or healthful (olive oil is thought to contain beneficial antioxidants) would not be affected, if their price were to be used as the benchmark for a minimum price for all fats.

How would this apply to sugars?
White sugar costs $1.91 for 500g (it gets complicated here because sugar becomes much cheaper in bulk, more nutritious sweeteners not so much.
Honey (the cheap clover variety) costs $5.19 for 500g. If that's too high a price for sugar, let's look at the least refined form of sugar - treacle. At $6.75 per Kg (price from cache), more than sugar (especially bulk sugar) but still cheap for 4,000 calories.

(Note: I am using prices from the Countdown website because they are available and internally consistent. I shop at Pak'nSave in Auckland so I'm used to prices being a bit lower. The examples I've used here are just that - examples).

From here on in, it's a job for experts. Foods have different prices per calorie at different sizes. It's relatively easy doing this with pure fats and sugars, it will be harder for me to calculate, say, for noodles vs potatoes without knowing the carbohydrate %. (I'm not an economist, I'm not even a shop assistant.)
But here we have white bread - only $1.48 for 600g.
And here's wholemeal bread, at $3.99 for 750g, about twice the price. Not much of a comparison here as the wholemeal bread is likely more processed than the white bread (read the label people, apparently it is no longer possible to bake bread without adding soy protein and a bunch of other non-traditional additives), but still, Government think it's healthier, and maybe it still is, and Government will be the ones responsible for administering any antiobesity food pricing system or tax.
And I'd rather they altered the food environment by pricing up the cheap, empty calories to be closer in price to the more nourishing ones, as opposed to taxing all fats (which would increase the cost of butter or olive oil more than that of soy or corn oil, because they cost more to start with), or taxing saturated fat, which would miss out gutter oils and cheap calories altogether. Similarly, taxing sugars would increase the price of honey or molasses more than that of white sugar or HFCS.

And yes, I know all the arguments as to why honey is so little different from sugar/HCFS as to make no difference. Those arguments apply if you think fructose is uniquely toxic, or if you're treating a condition for which carbohydrate needs to be restricted. But in the context of this discussion, how many people do you know who became obese eating honey without eating other junk carbohydrates? Honey has a flavour which tends to prevent it being overused in cooking in quite the same blithe way that sugar can be. And, low vitamin content and mere traces of minerals notwithstanding, it's a complete food for many of the bees in a hive. And it's well Paleo too, hunter-gatherers lap it up. Any regime of food pricing for health has to be about Lesser Evils, not Perfect Diets.

Based on these examples, we might come up with a minimum price of 0.1c per calorie (Kcal of course, food calories are always Kcal in physical terminology). This would give us a minimum price of $9.00 for a litre of soy or olive oil, $4.50 for 500g of butter, $4.00 for 1kg of sugar or honey. This conveniently rounded, decimal rate is almost perfect for these foods at present prices, and works across fat and sugar.

However, a Big Mac, at 492 calories, would have a minimum price of 49c. It has the more expensive protein in it, and the cost of extra labour and overheads, so it already costs more than that. Large fries would have about the same minimum price as a Big Mac, but are cheaper than Big Macs in reality (no meat, fries are just starch and oil). Processed fast food would need a higher rate, if you did want to target those calories. I'm not singling out McDonalds for effect; a KFC menu gives much the same result. But this does show targeting junk food won't catch the cheapest and emptiest calories, just some of the foods most likely to be addictive. And a change of price at the supermarket is a way of educating people about the quality of their food, which may carry over into the fast food environment. And far and away, calories consumed at home still outweigh those eaten at fast food joints.

So, back to the drawing board? I've taxed the limits of my rudimentary comprehension here. My brain hurts already. No more sums for me, but feel free to add your own.

Postscript; minimum pricing for one source of empty calories, alcohol, is already under investigation.

Much of the logic behind this initiative is similar to the the arguments I've raised.

 Let’s say the rate was set at $1.20. A 750 ml bottle of wine with 13 percent alcohol content has 7.7 standard drinks so could not be sold for less than $9.24. Not really much of a change there. However, a 3-litre cask of wine with 12.5 percent alcohol content contains 30 standard drinks so could not be sold for less than $36 – more than twice the current retail price.

And the drawbacks listed at the end of the article also apply to minimum pricing on food.

However, minimum pricing is not a magic bullet and is likely to have different effects on different populations. New Zealand is likely to be far more successful in reducing the use and misuse of alcohol across the spectrum if minimum pricing is introduced alongside a wider suite of policies.

For starters, without the recommended increase in the excise tax on alcohol or other similar measures, the additional revenue gathered under minimum pricing goes to the alcohol producers. In Canada, the state is the retailer, so this is not an issue. However, in New Zealand, this would be a lost opportunity for government, where even a small price increase is likely to result in significant additional revenue. That revenue would go a long way towards funding other harm-reduction activities, such as treatment, prevention or education. Perversely, if left in the coffers of the alcohol industry, it could be spent on measures designed to increase alcohol consumption (for example through increased expenditure on marketing).

Does reductive stress drive an adaptive inflammatory response, in depression linked to diet and lifestyle?

Everyone knows (I hope, because if they do it will save me a lot of time explaining) that inflammation can cause depression by activating the enzymes that degrade tryptophan, thus depleting the brain of serotonin.
Basically, macrophages hoover up tryptophan and pass it through Indoleamine 2,3,-Dioxygenase (IDO), where it is broken down. This is the pathway for the synthesis of niacin and nicotinamide, which is used to make NAD+.

(Note the other product, picolinic acid, thought to assist in absorption of minerals chromium and zinc)

There is the "sickness behaviour" explanation, whereby this response to infection, by making us less active, assists recovery, and the "sequestering" explanation whereby the macrophages act to deny tryptophan to pathogens, so that they don't have the advantage of extra NAD+. However, inflammation has many forms, and neither of these explain the response to chronic inflammation, when more activity and nicotinamide supplements are usually beneficial (nicotinamide seems to help in fighting infections too).



Supposing you are in the state known as reductive stress (not enough NAD+, too much NADH). This is associated with metabolic inflexibility, metabolic syndrome, and so on.
Reductive stress is mentioned by Peter D in this post. It is associated with fatty liver (steatosis) of chronic Hep C infection here, in these words:

the impairment of NADH oxidation to NAD, with consequent NADH accumulation, is a characteristic figure of mitochondrial dysfunction occurring in fatty liver due to high fat diet (HFD) in rats*.
So, how can NADH be converted back to NAD+ in these states? If lactate is available, metabolising this will restore NAD+, if ketone bodies are available, ditto for their interconversion (so exercise or carbohydrate restriction/fasting are protective against reductive stress). Electrophilic methyl groups in the diet - choline, carnitine, SAMe - may accept the H+ from NADH to form methane, which is dissipated.
But electrophilic methyl groups are hard to come by in the type of diets that cause reductive stress. No choline in flour, sugar, or vegetable oil. (Brilliant analysis of why this matters by Paul Jaminet here, also explaining that "high fat diet (HFD) in rats" line above*).

Also, fresh NAD+ can be supplied from outside the cell. From B3 if you're supplementing or eating good food (in which case your cells shouldn't have easily got into a reductive stress state, but requirements for B3 are unusually high for a co-enzyme vitamin). Or, if you're in the fasting state or your dietary B3 is inadequate, from tryptophan via IDO (Tryptophan 2,3-Dioxygenase is the hepatic equivalent). Which inflammation will upregulate.

So the hypothesis is, that reductive stress is an emergency (perhaps mimicking pellagra) that warrants an inflammatory response if this is what it takes to supply extra NAD+. But this process can not only deplete tryptophan and serotonin, but also produce a number of intermediate compounds that can are potentially neurotoxic.

The concentration of potentially neurotoxic compounds, such as 3OH-kynurenine, 3-OH-anthranilic acid, and quinolinic acid (QUIN) that are formed along the metabolic pathway leading from tryptophan to NAD (the kynurenine pathway) significantly increases in blood and cerebrospinal fluid of patients affected by a number of inflammatory neurological disorders and in animal models of immune activation.
So what is the messenger that reductive stress state cells produce, which triggers IDO in macrophages?
Why not the extra superoxide that is produced? This potentiates NF-kappaB,

Under normoxic conditions, NFκB is bound to one of several inhibitory proteins (e.g., IκB) that prevent its nuclear translocation. Hyperoxia or elevations of ROS cause the ubiquination and destruction of the inhibitory proteins, freeing NFκB and allowing it to bind to target gene promoters.

These target genes include INF-gamma and TNF-alpha. INF-gamma drives IDO in macrophages.
Nicotinamide is an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) that, through enhancement of nuclear kappa B-mediated transcription, plays a pivotal role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Through interaction with CD38 and inhibition of IL-1, IL-12, and TNF-α production, nicotinamide produces a mild TH2 bias. 

(in other words, the product of the inflammatory cascade that begins with reductive stress will inhibit it.)
So this may be part of a homeostatic survival mechanism in B3 deficiency (pellagra), which reductive stress imitates. In which case inflammation and depression is secondary to metabolic disregulation in diet-and-lifestyle related diseases. It is, so to speak, a perfectly natural, adaptive consequence of eating the wrong things and forgetting to exercise.

Edit: Aubrey de Grey's mitochondrial theory of ageing describes a mechanism by which surplus electrons from cytosolic NADH can be exported from the cell, recycling NAD+, via the plasma membrane redox system (pdf). Jettisoned into intercellular space, the electrons combine with O2 to form the superoxide reducing radical; reduction of transition metals (ferretin, ceruloplasmin) by superoxide also creates conditions for generation of oxidising radicals such as hydroxyl and peroxide. (note that RBCs lack the ability that other cells have to transfer electrons to O2 and form superoxide; RBC PMRS is an antioxidant system, other cell-types' PMRS are more likely to produce pro-oxidant effects)
In both that paper and this one, by two different sets of authors, there is a role in the PMRS for ascorbic acid (AA) and its oxidised
form dehydroascorbic acid (DHA is the product of 2-electron oxidation, the 1-electron product of AA is a free radical that becomes more common in the senescent leaves of plants pdf.) 

The authors hypothesize that the increased PMRS in erythrocytes during aging may be a protective mechanism of the system for efficient extracellular DHA reduction and ascorbate recycling under condition of increased oxidative stress.

And, perhaps, increased cycling of ascorbate is also a response to reductive stress. Oxidative stress, when not adaptive, as in the immune response, or toxic in nature, is the product of reductive stress, and both are increased by hypercaloric intakes of micronutrient deficient diets.