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Wednesday, 26 February 2014

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; < 0.001; and OR 1.016; 95%CI 1.001–1.031; = 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.

Thirdly, the heating of polyunsaturated oils produces peroxides which directly promote liver inflammation.

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.

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.

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:
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      

(* 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 (). 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 (). Conversely, activation of CB2receptors exerts antifibrogenic and antiinflammatory effects in experimental models of liver disease (). 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. () 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.


Tucker Goodrich said...

"After increasing saturation of dietary fats..."

I've noticed the same thing. Burns have less impact, cause less damage, and heal faster. Blisters I get from wearing shoes also hurt less and heal faster.

Additionally, as someone who burned easily in the sun, sunburn has decreased markedly. I used to get severe sun burn after as little as 40 minutes in the sun, I can now go for hours without protection and without burning. This happened within six weeks of adopting a low linoleic-acid diet.

It's been a very nice change.

tess said...

fascinating stuff, George!

Wout Mertens said...

George I cannot help but wonder if you would have gotten an answer had you ended your email just before the last paragraph where you talk about yourself :)

Fascinating stuff, thanks for posting!

Anonymous said...

Thanks, George. You inspired me to look through your blog for studies to send to my relative who has liver cancer.

Very useful. Cheers.

Puddleg said...

Yes Wout, that's quite possible and my communication with Dr Yu about cholesterol may have been more successful because more circumspect.
Chip, I remember a paper where Burton Berkson treated secondary liver cancer with alpha lipoic acid and LDN, it's on Pubmed

Anonymous said...

Thanks for that, found them.

Also found this -

Have some reading to do.

Puddleg said...

This blogger has been on LDN plus ALA for Hep C for some time, and has attended Dr Berkson's clinic

So you can get some idea what his protocols are like. There is a bit more to it than just those 2 supps, other vitamins and minerals, diet and lifestyle advice, are supporting their action, but nothing unusual.

The supporting protocol for cancer is probably similar to the Hep C one here, with ALA + LDN replacing ALA + selenium + silymarin, though some selenium for liver cancer makes sense as hepatoma cells can survive selenium deficiency that kills healthy hepatocytes, exerting selection pressure towards cancer, especially with HCV and HBV which sequester selenium.

Des said...

You just missed the low carb event in Auckland

Puddleg said...

Yeah I did, I followed it on twitter and on the blogs of participants and realised what a fantastic batch of presentations, I'll try harder to get to the next one!

raphi said...

Hi George,

As always, an interesting fusion of ideas - seemingly disparate at first - which come together for an interesting story.

[Had that paper too “Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity Anita” - great stuff!]

Your “heavy (daily) pot smoking dangerous in presence of liver injury” paper caught may eye.

I’d like to point a few things out after going through it (partially):

Honestly, I’m not impressed with it.

A big issue is that NO ONE smokes ‘just hash’ or ‘just pot’ —- it’s ALWAYS mixed in with loads of tobacco unfortunately…and cannot be separated out statistically (as hard as one may try).

“Moreover, occasional cannabis smoking did not emerge as an independent predictor of FPR, although this group of patients had similar disease duration compared with daily users. As reported in several studies, prevalence of excessive alcohol intake was high in cannabis users.”
-I think that last sentence says it all; currently, it seems impossible to truly separate the variables of pot smoking with the other obligate unhealthy health behaviours accompanying (daily or not) cannabis consumption. A multivariate, regressive analysis isn’t able to account for these differences as the socio-political context renders pot smoking-unhealthy behaviours much too intertwined for this type of analysis to be reliable.

“Finally, severe fibrosis (>F3) was also predicted by daily cannabis use (OR=2.5 [1.1-5.6]; P= 0.034), independently of […] tobacco smoking.”
-You’d expect this effect to hold true (to some extent at least) in people without HCV or other liver issues, but we don’t see this by any stretch of the imagination throughout the literature of anecdotally.

“daily cannabis use (OR=3.4 [1.5-7.4]); excessive alcohol intake (OR=2.2 [1.1-4.5])”
-this would indicate that your more likely to harm your liver smoking pot daily than consuming alcohol in ‘excess’…well, this is simply very very wrong and unsupported (epidemiologically, biochemically, anecdotally etc.,)

- The study is of the epidemiological & pro/retrospective data type - not that those aren’t useful, but they certainly don’t linking claims such as “it has been shown that endogenous activation of the cannabinoid system plays a role in the pathogenesis of portal hypertension associated with cirrhosis via CB1-dependent splanchnic vasodilation” with ‘cannabis consumption’.

- Their effects are IN VITRO and obtained with (at most) 2 cannabinoids…..out of the 60+ that exist but haven’t been studied yet (ignoring the terpines, polyphenols etc.,)…and take such effects to represent the effect of the whole plant. Isn’t that like the common mistake of studying an isolated vitamin/hormone and then exporting those conclusions to the whole foods containing them?

Puddleg said...

Hi Raphi,

I agree with that analysis but included that paper as representative of another I've seen in print but not online. Hepatologists I generally trust are giving that advice and saying the evidence is strong, and if it is foolish advice it is the first time they have subscribed to such, so I thought it deserved an airing.
I suspect that IF there is something to it, it is specific to HCV.
CB1 was expressed in all patients with CHC and levels were 6-fold higher than in controls (P<0.001). CB1 expression increased with fibrosis stage, with cirrhotics having up to a 2 fold up-regulation compared to those with low fibrosis stage (p<0.05). Even in mild CHC with no steatosis (F0-1), CB1 levels remained substantially greater than in controls (p<0.001) and in those with mild CHB (F0-1; p<0.001).

However the claim that the effect of cannabis exceeded or approached that of alcohol is totally inconsistent with the evidence of anyone's eyes. Alcoholics with HCV get cirrhosis first and most. Definitely.
But worth considering, I think, for individuals who want to know what else they could be tweaking to slow progression.

I don't know that there is a strong correlation of tobacco smoking with fibrosis - I've looked for this briefly before and it hasn't leapt out at me. And where I live tobacco use with pot isn't that common, mostly Kiwis who picked up the filthy habit overseas.

raphi said...

@Geroge Henderson

“Alcoholics with HCV get cirrhosis first and most. Definitely.” —> I’d go a step further and say that I haven’t ever (anecdotally, epidemiologically or clinically) observed someone getting some form of liver inflammation via the consumption of cannabis alone (& god knows I’ve heard all sorts of weird unsubstantiated health claims regarding the ill effects of the ‘devils weed’ :p).

As for tobacco and fibrosis - yeah, I haven’t heard of that specific link either. However, simply considering how inflammatory & radioactive tobacco is, it isn’t a big leap to to see how it could behave as a strong contributing factor (to all sorts of ‘-itis’…).

I haven’t gone through the study you linked to entirely, I mostly looked at their methods, results & discussion sections: they’ve convincingly shown CB1 up-regulation via mRNA (PCR) analysis comparing a treatment & control group. I think this simply points us in the direction of considering the role of the CB1 receptor, not a prescriptive solution (i.e., ‘you should avoid CB1 agonists’ or ‘you should incorporate CB1 agonists’).
Considering how potent a general anti-inflammatory cannabis is (the whole plant & some extracts) and that (as far as I know) this study or others haven’t tried to disentangle the chicken-&-egg, cause-or-effect relationship between CHC & CB1 agonists I wouldn’t see that as a ‘safe bet’ to go out of your way to avoid cannabis if suffering from this condition…it isn’t implausible after all that the receptor is upregulated as a ‘defence’ or ‘harm mitigation’ response. Of course, I’m speculating here…but with loads of other data to support such a mechanism in mind (if you wish to explore further, I could go on a pubmed safari & link some stuff back - just ask: @raphaels7)

Also, this groups results would then need to address all the positive anti-inflammatory, pro-selective-apopotosis capacity of CB1/THC & other cannabinoids…so you see, I completely understand your cautionary recommendation, but can also easily see how quickly counter-evidence might actually suggest the exact opposite (not uncommon i medicine of course). & yes, the paper isn’t purporting to address all of my claims, fair enough. :)

As always, thanks for the discussion George, I look forward to more of your posts.

PS: on a different note - interesting stuff RN is putting up at FTA about glycogen levels in raw animal parts…I wish he’d simply drop the straw man argument that LC/keto diets are ‘lacking in fibre’, a pity - it makes an issue more divisive than necessary :s

Puddleg said...

Yeah it is possible that low levels of THC inhibit the CB1 action that promotes fibrosis at higher intakes.
Natural cannabinoids are only weak CB1 ligands, so they could be protective in the presence of, say, elevated anandamide.
And there's an omega 3 analogue of anandamide, which is probably desirable in this scenario.
I don't see light pot smokers having faster fibrosis progression at all, but the heaviest smokers, that might be happening - but can't compete with alcohol, or addiction to junk food promoting fibrosis through diabetes.
Did they control for the munchies?

Puddleg said...

About RN, I've also transitioned from VLC to eating more potato.
The difference is, I haven't forgotten how I got here.
I couldn't have gone from eating high-carb to eating lower carb with potatoes - in fact, that was exactly what I tried and failed to do (felt no better) until I a) read Dr Atkin's Diet Revolution b) read Mary Enig, learned from her about Nanji and French and discovered Health Benefits of Saturated Fat.
Potatoes are health food - BUT - "you can't get there from here".
The best way to get there is through VLC.
This is what RN, Jaminet, and everyone else actually did IRL.
it's a process.

raphi said...

Very true - modern food environment doesn’t jive well with the munchies! Who ever had the munchies and ‘ate too much white fish & cabbage’?? I’d like to meet that person…

I very much like how you framed this a a process - recognizing the inherent learning curve.
I also avoided potatoes for some time when learning about LC principles. The only reason I incorporated them back in is that I do so for 1) variety 2) taste & because 3) the amounts/frequency with which I consume them don’t detract from a LC (or even Keto) eating approach as far as I can tell - NOT because I feel or think I ‘need’ more glucose. Win-win? Hopefully…

Again, I read RN & Tim Steele’s adventures into the land of RS & anthropological evidence with great interest - hopefully the discourse will progressively leave behind the straw-man arguments of 1) keto/LC only being viable therapeutically & 2) keto/LC being nearly fibre free…well, we can’t have everything! Kudos on them though [leaving 1) & 2) aside]

Puddleg said...

Another factor might be that unsuccessful treatment with interferon seems to accelerate fibrosis progression, compared with successful treatment or even leaving well enough alone.
So it may be that this group, especially in the USA, smokes more medicinal cannabis, because they have more SFX to medicate.
Controlling for numbers of treatments and non-response seems essential to me. It's my impression that these are the largest risk factors of all.

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