Fish Oil, Krill Oil, and Hepatitis C

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

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

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

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

For one thing, they all inhibit HCV replication.

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

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

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

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

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

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

(click on "look inside" link).

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

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

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

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

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

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

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

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

Anyhoo; what to recommend?

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

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

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

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

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

My Dietary Recommendations for Liver Health

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

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

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

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

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

or are suspected, to prevent it.

In general terms

1) Protein is very protective of the liver,

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

sugars can be harmful, and

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

There are 3 specific substances to minimize or avoid:

Minimize:

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

juice, honey, as well as sweet fruit).

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

insulin response to glucose; high consumption of fructose can cause

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

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

fructose for most people.

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

promotes VLDL expression, increasing the release of virus to the

bloodstream).

Minimize:

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

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

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

occasional nuts and seeds. Vegetable oils contain large quantities of

omega-6 lineolic acid, which promotes inflammation and suppresses

omega-3 fats.

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

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

When large amounts of polyunsaturated fats are added to alcohol or

drugs, liver damage and fibrosis are increased.

Persons with Hepatitis C show increased fibrosis and worse responses

to treatment with higher PUFA content of the diet.

Vegetable oils decrease LDL and HDL cholesterol, while saturated

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

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

response to treatment.

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

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

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

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

cocoa, and coconut is protective.

Minimize, and if possible Avoid:

Gluten grains.

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

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

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

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

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

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

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

contains added iron.

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

which allows bacteria and toxic undigested proteins to enter the

bloodstream from the gut.

Parts of these bacteria called LPS can trigger inflammation in the

Liver.

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

gluten sensitivity disease. Coeliac and non-celiac gluten sensitivity

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

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

with Hepatitis C.

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

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

so many digestive challenges.

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

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

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

starches, and green vegetables are richer in protective

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

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

tolerate other gluten grains can tolerate oats in small amounts.

Some special foods that protect the liver:

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

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

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

cirrhosis. Red meats are best.

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

protective against fibrosis.

Coffee consumption protects against fibrosis and cirrhosis from

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

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

tea.

DHA from oily fish is protective against fibrosis in moderate

supplement doses but may increase it in excessive amounts.

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

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

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

Beetroot contains betaine and some unusual and potent antioxidants,

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

15 minutes, roast for under 1 hour).

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

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

fermented soy.

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

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

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

Carotenoids, folic acid, and flavonoids protect against fibrosis and

are found in green leafy vegetables; sulfur compounds found in

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

immunity and protect against cancers.

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

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

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

and coeliac disease.

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

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

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

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

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

vegetables and berries are excellent foods. Prunes and raisins are

good dried fruits.

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

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

best varieties.

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

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

lack.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

rather than deep-frying.

Some references:

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

Alcohol and dietary intake in the development of chronic pancreatitis

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

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

search function)

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

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

Relationship between Dietary Beef, Fat, and Pork and Alcoholic

Cirrhosis; Bridges

Dangerous Grains; book by Hogan and Braley.

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

advice on supplements and drugs)

Applying principles of HCV virology to the Development of new

Antiviral Therapies; Stephen J. Polyak

(c) George D Henderson 2012


Feel free to use this.

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