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).