Tuesday, December 01, 2009

Cirrhosis and fish oil

The first paper in this post is just the abstract as Wiley Interscience are not particularly generous with access. There are lots of details about the diet (though not quite everything you would really want) in the second paper by the same group which is full text.

These people are using ethanol/fish oil as their model for alcoholic cirrhosis. Now I have been very rude about these models and I should be a little more consistent but, what the... While fish oil/ethanol is a bit strange as a diet the findings are exactly the same as for the corn oil/ethanol combo, nutrients which might warm the cockles of any modern cardiologist's heart.

Here is the first really impossible feat performed by the rats on booze. They can reverse both fatty liver and fibrosis of the liver. Stopping the alcohol intake does not do this UNLESS the fish oil is stopped and replaced with, you guessed, saturated fat. You can choose palm oil or coconut oil, either will do. Dextrose instead of alcohol won't hack it.

Let's pretend humans and rats are the same. Let's pretend fructose and alcohol are the same. Let's pretend fish oil and corn oil are the same. Good game. Probably true.

Let's think about human fatty liver progressing to hepatic fibrosis and inflammation, triggered by fructose and corn oil. I think this is common. Going to a low carb diet to treat fatty liver will clearly fail if all you do is stop the fructose. Something else is needed, something difficult to do in the current nutritional climate. You have also got stop the consumption of corn oil. You have got to eat saturated fat.

Now that is not so easy in a saturophobic climate. How many people with fructose induced hepatopathy, who have been told that the cause is "unknown" are willing to adopt a diet which is based on that ultra demonic, evolutionarily catastrophic monster: PALMITIC ACID? OMG it might increase your LDL. Better die of cirrhosis than increase your LDL!

Anyhoo, back to the fishoil 'n' booze nourished rats:

This paper tells us much more about reversing fish oil/alcohol induced liver damage in rats. The core finding is that you don't even need to stop the alcohol. Just get rid of the fish oil, provided you replace it with saturated fat. So theoretically you could continue to consume fructose while limiting your corn oil consumption, if it is correct that hepatic injury is core to metabolic syndrome...

From my point of view, if we are going to eat real foods which contain some PUFA and some fructose, simply limiting both to easily achievable limits seems a whole load better than the total elimination of one to allow extra consumption of the other...

As always, I have the greatest respect for Kwasniewski and I suspect the concept of liver disease being irreversible is completely specific to the context of the saturophobic modern nurtitional dogma. Waiting until your liver is a minute scrap of scarred fibrous tissue with a mass of non-functional hyperplastic nodules and is at end stage cirrhosis is a bit too late. Having a "mysterious" elevation in ALT is a good time to reach for the beef dripping.

NAFLD and NASH are candidates for reversal.

I'll kick around a few ideas about PUFA, endotoxin and cirrhosis in the next post.

Oh, and fish oil: I think some DHA is a good idea, it has lots of uses in cell membranes. Drinking it by the tablespoon is not something I would recommend! Getting 30% of your calories as fish oil is OUT. Do not do this.

Peter

37 comments:

JB said...

Peter, very good on fish oil.

You likely have seen Ray Peat's write up on the subject, but if not:

http://raypeat.com/articles/articles/fishoil.shtml

Cheers! Brad

Peter said...

Brad, If Peat would cite references which actually say what he claims in the text I'd have a lot more time for him! Unfortunately...

Peter

Dr. B G said...

Peter,

Do you think it is a dose effect? Not enough vitamin E and antioxidants to quell the lipid peroxidation?

In human and rat trials both EPA and DHA or alone independently have been shown to reverse NASH/ NAFLD and on liver biopsy. Both EPA and DHA are the natural ligands for PPAR (which control TNFa, cytokines and NFKb).

J Clin Gastroenterol. 2008 Apr;42(4):413-8.

Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis.
Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T.

Recent studies have demonstrated that n-3 polyunsaturated fatty acids ameliorate nonalcoholic fatty liver disease. Although eicosapentaenoic acid (EPA), one of the major components of n-3 polyunsaturated fatty acids, is widely used as an antilipidemic agent, its single efficacy for nonalcoholic steatohepatitis (NASH) remains unclear. As such, we aimed to evaluate the efficacy and safety of EPA on 23 biopsy-proven NASH patients in a pilot trial. Highly purified EPA (2700 mg/d) was administered for 12 months and efficacy was assessed by biochemical parameters and liver histology. All patients completed the treatment with no adverse events, indicating acceptable tolerance to the treatment. After 12 months, serum alanine aminotransferase levels were significantly improved (from 79+/-36 to 50+/-20 U/L), and serum free fatty acids, plasma soluble tumor necrosis factor receptor 1 and 2 levels, and serum ferritin and thioredoxin levels, which may reflect hepatic oxidative stress, were significantly decreased. Body weight, blood glucose, insulin, and adiponectin concentrations remained unchanged. Seven of the 23 patients consented to undergo posttreatment liver biopsy, which showed improvement of hepatic steatosis and fibrosis, hepatocyte ballooning, and lobular inflammation in 6 patients. In conclusion, EPA treatment seems to be safe and efficacious for patients with NASH, largely due to its anti-inflammatory and antioxidative properties. To confirm these results, appropriately powered, controlled trials are needed.

PMID: 18277895


Of course... SATURATED FAT does so as well *BIG WINK*!!

All the MCT oil trials I've looked at (like 3 or 4) improve liver function tests and there is like 1-2 MCT oil and coconut oil human NASH trials too. Butter? I think butter would work too. Butter + EPA DHA. Bangin!

Good post. You know NASH is considered a metabolic syndrome criteria by some experts. It is a true model of insulin resistance. I don't plan on making foie gras out of mine though :)

-G

Cristian Stremiz said...

Taurine, my favourite supplement, is able to reverse the alcoholic liver disease in rats. And it's damn cheap! :-)

1. Amino Acids. 2009 Mar;36(3):457-64. Epub 2008 May 29.

Effect of taurine on alcoholic liver disease in rats.

Wu G, Yang J, Sun C, Luan X, Shi J, Hu J.

College of Animal Science and Veterinary Medicine, Shenyang Agricultural
University, Shenyang, China.

To investigate the effect of taurine on alcoholic liver disease in rats, male
Wistar rats were administered alcohol intragastrically for 3 months. The effect
of beta-alanine-mediated taurine depletion and taurine administration on the
development of alcoholic liver disease was examined. It was found that taurine
administration produced lower levels of aspartate aminotransferase and alkaline
aminotransferase than that of the untreated group. In addition, the levels of
hepatic total protein, glutathione and superoxide dismutase were higher in the
taurine treated groups than those in the untreated control or the taurine
depleted groups, while hepatic malondialdehyde content exhibited the negative
effect. Moreover, the concentrations of hepatic hydroxyproline, serum hyaluronic
acid, interleukin-2, interleukin-6, tumor necrosis factor-alpha and laminin were
all decreased in the taurine treated groups. The pathological changes showed that
the percentage of fatty degeneration and inflammation in the taurine groups were
lower than that of the control, taurine depleted and automatic recovery groups.
These in vivo findings demonstrate that hepatic disease caused by chronic alcohol
consumption can be prevented and cured by administration of taurine.

PMID: 18509591 [PubMed - indexed for MEDLINE]

Cristian Stremiz said...

Plenty of butter and a spoon of taurine it seems to be the best way to go.

1. Amino Acids. 1998;15(1-2):53-76.

Taurine: protective properties against ethanol-induced hepatic steatosis and
lipid peroxidation during chronic ethanol consumption in rats.

Kerai MD, Waterfield CJ, Kenyon SH, Asker DS, Timbrell JA.

Department of Pharmacology, School of Pharmacy, University of London, United
Kingdom.

Alcohol was administered chronically to female Sprague Dawley rats in a
nutritionally adequate totally liquid diet for 28 days. This resulted in hepatic
steatosis and lipid peroxidation. Taurine, when co-administered with alcohol,
reduced the hepatic steatosis and completely prevented lipid peroxidation. The
protective properties of taurine in preventing fatty liver were also demonstrated
histologically. Although alcohol was found not to affect the urinary excretion of
taurine (a non-invasive marker of liver damage), levels of serum and liver
taurine were markedly raised in animals receiving alcohol + taurine compared to
animals given taurine alone. The ethanol-inducible form of cytochrome P-450
(CYP2E1) was significantly induced by alcohol; the activity was significantly
lower than controls and barely detectable in animals fed the liquid alcohol diet
containing taurine. In addition, alcohol significantly increased homocysteine
excretion into urine throughout the 28 day period of ethanol administration;
however, taurine did not prevent this increase. There was evidence of slight
cholestasis in animals treated with alcohol and alcohol + taurine, as indicated
by raised serum bile acids and alkaline phosphatase (ALP). The protective effects
of taurine were attributed to the potential of bile acids, especially taurine
conjugated bile acids (taurocholic acid) to inhibit the activity of some
microsomal enzymes (CYP2E1). These in vivo findings demonstrate for the first
time that hepatic steatosis and lipid peroxidation, occurring as a result of
chronic alcohol consumption, can be ameliorated by administration of taurine to
rats.

PMID: 9871487 [PubMed - indexed for MEDLINE]


And taurine (rich in seafood) would explain better than omega-3 the epidemiological studies linking health and marine food consumption. The japanese think so.

1. Adv Exp Med Biol. 2009;643:13-25.

Taurine as the nutritional factor for the longevity of the Japanese revealed by a
world-wide epidemiological survey.

Yamori Y, Liu L, Mori M, Sagara M, Murakami S, Nara Y, Mizushima S.

Mukogawa Women's University, Japan. yamori@cardiacstudy.com

The initial observation that taurine (T) prevented stroke in stroke-prone
spontaneously hypertensive rats (SHRSP) led us to study the effects of T on
cardiovascular diseases (CVD), as well as the epidemiological association of T
and mortality rates, by using the data from WHO-coordinated Cardiovascular
Disease and Alimentary Comparison Study, which covered 61 populations in 25
countries. In this study, 24 hour urine (24-U) samples were examined along with
biomarkers of CVD risk. The mortality rate from ischemic heart disease (IHD),
which was lowest among the Japanese compared to the populations of other
developed countries, was positively related to total serum cholesterol (TC) and
inversely related to 24-U taurine excretion (24-UT), as well as the n-3 fatty
acid to total phospholipids ratio of the plasma membrane, both biomarkers of
seafood intake. Analysis of 5 diet-related factors revealed that TC and BMI were
positively associated with IHD mortality in both genders while Mg and T were
negatively associated with IHD mortality. TC and sodium (Na) were negatively and
positively associated with stroke mortality, respectively. 24-UT was negatively
associated with stroke mortality. These five diet-related factors explained 61
and 49% of IHD and stroke variances in male, 63 and 36% of IHD and stroke
variances in female, respectively.

PMID: 19239132 [PubMed - indexed for MEDLINE]

Peter said...

G, yes, I'm sure it is dose related. I look to the Lyon Diet Heart study to give us a ball park of acceptable limits. For omega 6 I suspect the lower the better but zero shouldn't be needed. Then some DHA but I doubt we know how much/little on a low omega 6 background...

Peter

rosenfeltc said...

Peter please excuse my ignorance but would COD liver oil essentially have the same effect on the liver as fish oil then?

pyker said...

Excellent. I was looking for an excuse for kebab night to come early this week!

Linda said...

Okay, not sure I understood most of that. So I know to stay away from corn oil, don't use it anyway except for mayo, but not sure about the fish oil. It is keeping my cholesterol down. I guess I should use more of the CO instead. First I have to see what they say is wrong with my liver. Thanks for the info. but the discussion is beyond me. Linda

Robert McLeod said...

Another concern that wasn't addressed in the article is the question of whether the fish oil was rancid or not. This should be a valid concern for both n-6 and n-3 oils, since neither group of molecules are stable against oxidation at room temperature. And of course there's the whole hydrogenation of vitamins issue at play too. I sort of consider this issue a modern parallel to the old, "let's feed rats Crisco and call it saturated fat," saw.

I would like to know what the proposed protective mechanism for saturated fat is, if there is one? Based on the findings from Framingham and MRFIT all I'm comfortable in saying is that saturated fat displaces other calories that may be harmful.
I.e. I think saturated fat is completely neutral health-wise.

Looking at Table 2 in this study, the rats fed fish oil and dextrose had no liver problems whatsoever, so ethanol is still the ultimate causative factor here. And those fed medium-chain triglycerides did better than those fed palmate after six weeks.

CoreyLH said...

I began my search for a proper diet after consecutive annual physicals showed progressively high ALT. By getting over saturophobia (love that word btw)and avoiding corn anything I have lost both the high ALT and 75 lbs! Never felt better.

rosenfeltc said...

Linda are you serious? Have you even read Good Calories Bad Calories by Taubes? Lowering your cholesterol doesn't prevent heart disease, in fact it may even be healthier for it to be a bit higher than what the medical industry would like

Kurt G. Harris MD said...

Hi Peter

I think it is high time you find a new name for your blog.

lipids include nasties like corn oil.

How about:

Hyperlongchainsfa

Hyperbeefdripping

Hyperruminantfat

Peter said...

Hi Christian, thanks for the links. They make me think of cats and lipidosis again, this time from the taurine perspective.

Rosenfeltc, that depends. I've seen studies where the A and D content of CLO undo the potential damage of high dose omega 3s but again, not to hand.

Pyker, yes, Friday is some time away. I'm not sure this rationing business is good for me. Maybe waiting is wrong...

Linda, The two common causes of fatty liver are fructose and alcohol and PUFA, of any sort, convert it to inflamed liver. The dose has to be high for the omega 3s and I have no objection to 5ml of fish oil or CLO a day. Getting it up to 30% of your calories or up to three tablespoons a day seems risky to me. Again, there were minimal problems in the rats unless you added alcohol (or I guess fructose).

Robert, yes, but the same applies to people downing CLO from a room temperature opened bottle. I agree, you do seem to need that trigger and as these were alcohol studies, that's what they used. Fructose probably works just as well. There was a comment somewhere in the papers that a fatty liver is the pre requisite for inflammation, and that PUFA were needed to generate the lipid peroxides to activate NF-kappaB and get to steatohepatitis.

CoreyLH, Glad to hear it. I wonder about pre and post change hepatic ultrasounds... Biopsies would be even better but, as an anaesthetist, no one would get near my liver with a needle without a damned good reason and 8 units of matched blood available!

Kurt, well yes but I like Hyperlipid. I've sort of grown attached to it! And it does roll off the tongue quite well...

Peter

Nate said...

30% of your calories as fishoil... mmm can you imagine your breath after that, not even the flavoured ones could save you :P

...i've got that first article if your interested in looking deeper.... i'lll leave my email on my profile for a 2 days.

MCT said...
This comment has been removed by the author.
MCT said...

great post

Dr. B G said...

Well. Only rats get 30-35% fish oil... rat-breath?




Peter,

You should consider going into the market for hang-over remedies. Package up some beef tallow (or flavor-less MCT or palm oil)!

(Bacon and burgers are the best remedy for me *wink*)

blogblog said...

Like virtually every other paper published on nutrition both these papers are are the worst type of junk science. They have absolutely no basis in reality or relevance to human health.

There is absolutely no valid scientific reason for using rats as a human nutritional model. In fact there is no other mammal that is even a vaguely realistic model for human nutrition. Humans and giant pandas are both unique in that our natural diets are radically different to our nearest relatives. Pandas are bamboo eating bears and we are carnivorous apes.

The only reason for using rats is that they are small, short-lived and most people hate them. This means anti-vivesectionists won't protest too much when extremely cruel and utterly irrelevant "scientific" experiments are performed on rats.

The Pharmacology study is absolute BS. No human could possibly consume 10-16g/kg/day of ethanol. This is equivalent to a 70kg man drinking 15-25 litres of beer a day. Any human would be dead within hours from acute alcohol poisoning.

Likewise no human is ever going to get 35% of their calories from fish oil - it would result in chronic diarrhoea. Even the Inuits only managed a maximum 5% of their calorie intake as fish oil - none of it in liquid form.

blogblog said...

A fatal dose of ethanol for humans is 400mg/kg. For rats it is 7000+mg/kg - almost 20x as high. In fact rats are so tolerant to most toxins that any comparison to humans is utterly meaningless.

MCT said...

so do you propose we test new hypotheses with humans? that we'll make faster progress this way?

Peter said...

Blogblog,

This would be a valid comment if it weren't for the fact that fish oil was being used as an equivalent of the corn oil used in the first paper. When corn oil was being used it was able to cause pathology at levels of intake easily achievable with generous mayonnaise usage, around 15% of calories. I would agree that 0.1mol/l is a lot of alcohol but clearly less is certainly effective in humans (unless you would argue that alcohol is harmless to humans) and fructose appears to be a perfectly reasonable substitute. It would be nice to think that corn oil and alcohol were harmless to humans, despite their being so toxic to rats, but that's wistful thinking.

Peter

Peter said...

I would suggest that it would be quite reasonable ask a group of people with fatty liver disease to eliminate all vegetable oils from their diet as far as possible. You would have to replace these calories with something. Saturated fat would minimise your variables compared to using carbohydrate.

Peter

Robert Andrew Brown said...

Great blogs Peter


http://jpet.aspetjournals.org/content/299/2/638/T2.expansion.html

Fish oil-dextrose
Fatty liver 0.02-b Necrosis 0.01  ± 0.012-b
Inflammation 0.2  ± 0.12-b

"Control animals fed the fish oil-dextrose diet (group 5) showed no pathological changes."

It is the alcohol and not the fish oil that is leading to the condition. (-:

I have no problem with the idea 30% of cals from, fish oil is not a good idea, but do believe based on an argument of shoreline ancestry, and a pile of trials on a huge range of subjects that we are designed for some DHA in our diet, but can on a nutrient dense paleo diet just manage without it (but not with high alcohol intake which helps remove DHA form the brain and other tissues).

I am also believe unadulterated saturated fats from natural sources have an important part in human metabolism.

Eating fish is in the natural order of things, we tend to forget mass production of alcohol is probably not a widespread paleo trait.

caphuff said...

can someone please give an executive summary of all this?

(BTW, by "executive summary" I mean pretend you're explaining it to a 5-year old.)

Peter said...

Yes, it doesn't come over in the posts but we have two labs here, both using extreme "models" to get detectable changes in a few weeks. The models look to be interchangeable to me and, while I hope no one would even remotely consider taking 30% of their calories as fish oils, this does not seem an impossible achievement using corn oil. They do the same. In many ways it would have been much better if both labs had used corn oil, but they didn't!

If we assume that the Lyon Diet Heart Study achieved its effects through altering omega 3 to 6 PUFA ratios while keeping omega 6 PUFA below 8g/d, then a couple of grams a day of omega 3s from fish oil should be fine in my book. Bearing in mind that fish oil is far from 100% omega 3s, this is roughly where I got my 5g/d fish oil from...

I agree re sat fats, palmitic acid looks to be as much a hormone as a nutrient to me, it's one of the concepts DrBG puts nicely...

Peter

Caphuff, don't drink corn oil, do eat saturated fat. This should minimise booze induced damage but better minimse the booze too...

Dr. B G said...

Cristian!

SCORE! Taurine is great stuff. Do we neolithic humans get our quota??! I dunno...

These lion cub babies were dying from rickets despite vitamin D supplementation until taurine was added as cold-pressed cod liver oil.

Rickets in lion cubs at the London Zoo in 1889: some new insights.
Chesney RW, Hedberg G.
Pediatrics. 2009 May;123(5):e948-50.





Peter,

I've thought about this. Yeah scarey. I love the outcomes from Lyon Diet Heart 76% risk reduction of death and cardiac events including cancers, suicide and fatal accidents (almost as impressive as niacin/PUMA-G KB agonism HATS trial 2001 NEJM with 90% risk reduction in death and events).

But... basically Lyon Heart is a flaxseed oil trial not really fish oil EPA DHA. The margarine was ALA and the diet had minor but potent reductions in toxic n-6 (junk food, grain-fed sausage and deli meats?). They ate a little more fish per week but not much. An extra 1 serv perhaps?

The consensus I get from centarian studies and those like Lyon Heart are that each society has sources of: SFAs (short med long chain) EPA DHA ALA, taurine, ocean minerals (incl iodine chromium Mg Se etc) and sunlight. Crete Okinawan Belgium France and Sweden come to mind... I don't know about NASH but these have the longest lifespans and lowests CAD and cancer... Sunlight maybe the big difference for the northern countries but perhaps the EPA DHA makes up for it for the Inuit and other trad'l northern H-G? I think apoE4 types requires less vegetation and perhaps less ALA some evidence suggests.

I don't understand this article yet -- stigmasterol is the heat-labile Factor 'X' as identified by Weston Price in clover-fed butter oil. (Taurine is in raw grassfed butter and meat too) Also they reduced the sat fat in the diet -- not good as we know for ALL apo E types (Krauss et al) but worst lipo effects I believe for apo E4.

http://jn.nutrition.org/cgi/reprint/139/1/13

-G

Dr. B G said...

(whoops...Wulzen Factor, not 'X' factor which is K2)

Peter said...

Hi Nate,

Thanks for the offer but it's arrived off blog. Kind of you to offer.

G and Robert, I have memories of Mercola suggesting CLO at some dose rate like 5ml/lb. For a big human that's a lot. The "fishy burp" should not be part of life! Some DHA, yes. Sorry these posts and my return comments seem to be totally random in order!

And re taurine and rickets, we need to talk vegetarians in Glasgow along these lines. Very interesting. I suspect humans are not as hot on taurine production as we supposed to be!

Lyon study, the big confounder is also that the intervention group appear to have been told to eat Food, as opposed to the sort of cr@p that gets the French equivalent of AHA approval for the usual care group. I suppose we do need the study to be replicated too. It is a bit of a one off in diet interventions!

Peter

Prostato said...

Hmm, what was the ratio of Omega 3 to "saturated fats" (palmitic and/or stearic) in these rat experiments?

Marco said...

Hi friends, I love these blogs about diseases and cities, when I was in college did a very good study called liver cells, where I learned a lot about this subject

Martin said...

Hi Peter,

Alcohol (by far not excessive) and supplementing fish oil the last couple of years made me a lab rat just like the ones in the study. I developed upper right abdominal tenderness and face eczema.

I have been experimenting last few months with eliminating foods and came to the current diet of eliminating gluten, lactose, fructose and alcohol. Most eczema is gone but the abdominal tenderness persists. After reading your post (many thanks!) fish oil is now off too and it does make considerable difference. It is warrying to see that sometimes fish oil is recommended as treatment of intestinal permeability
http://www.ei-resource.org/articles/leaky-gut-syndrome-articles/intestinal-permeability-or-leaky-gut/

So far no lab results other than negative small intestine biopsy (made 3 months down the gluten free diet though) and negative abdominal ultrasound scan. As both conditions are not gone completely would you have some suggestions on what to do, read and eat (and not eat) next?

Peter said...

Hi Martin,

Butter is an excellent source of calories. Buying from a source produced anywhere other than the USA will get you enough DHA, especially if you also eat fish every few weeks. Shifting meat sources away from chicken/pork towards lamb and beef would help. Alcohol and sugar limited to recreational use rather than as sources of calories.

Absolutely no vegetable oils.

That's basically what I do.....

Peter

Hanna said...

what about krill oil instead of fish oil?

Peter said...

Hi Hanna,

So long as it is not a source of bulk calories I doubt it much matters. A few grams a day won't do much harm and might do a little good...

Peter

Nick said...

Hi Peter,

This is just a shot in the dark, really. A good friend of mine has stage 2 cirrhosis caused by hepatitis C. She does not drink alcohol but does eat a fair amount of PUFA (peanut butter). Right now she eats a lot of tapioca because it doesn't upset her stomach. Given that her cirrhosis is not caused by NASH, I'm wondering how much avoiding PUFAs might be worthwhile for her. She is about to start a very invasive treatment that includes interferon. She also eats a fair amount of dried prunes, which I imagine are fairly high does of fructose.

Any thoughts on what you would eat in this scenario?

Many thanks for your reply.
Nick

Peter said...

Hi Nick,

No one has any idea where to start on a query like this, certainly I would not expect anyone to take internet advice from some metabolic oddball like myself. If you friend really wants to look at matters beyond drugs for hep C they could do worse than starting with George's blog, he knows a great deal about hep C... And follow the links. Following advice is crazy, following links and understanding the implications before deciding what advice to take might well have some benefit.

George's blog:

http://hopefulgeranium.blogspot.co.nz/

Peter