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Thursday 27 June 2013

Cholesterol is a nutrient, not a food. Pork and cirrhosis revisited.

If HCV up-regulates HMG-CoA reductase, yet inhibits cholesterol completion, and if low cholesterol scores are associated with both hepatocellular cancer and poor response to treatment in people with chronic HCV infection (and much the same also applies to HBV), it seems reasonable that people with these conditions will benefit from cholesterol in the diet.

(Listen to a song that deserves to be famous - Sexually Attracted to Myself by Reader's Wives)

Eggs are well known as a food high in cholesterol, and counties where the population consumed most eggs had a 0.54 OR for cirrhosis in the China Study (if that's a correct extrapolation from -46). That's a whopping decrease, and probably meaningful, and cirrhosis in China mainly relates to chronic HBV and HCV infection.
Denise Minger points out that the average egg consumption associated with these results is only equal to 2-3 eggs a week. But then, that is an average, and the statistic will include people who ate more eggs and people who ate less. Eggs not only supply cholesterol but also choline, and choline deficiency is the most efficient way to create fatty liver disease experimentally. An animal fed such a diet cannot assemble VLDL particles so both lipids (especially oleic acid, both from diet and from DNL elongation of palmitate)  and cholesterol (synthesis is likely increased to try to shift the hepatic fatty acid load) accumulate, resulting in NASH, where crystallization of cholesterol in the liver is implicated. Fatty liver is pretty much the precondition for cirrhosis (5 OR), so the balance between cholesterol and choline (i.e. phospholipids) in the diet may be of importance.

File:Cholesterol.svg

A new paper has shown an association between dietary cholesterol and progression of cirrhosis in chronic HCV infection. I don't have the full text access and would love to see the raw data if anyone does have access, but in the meantime will speculate on what it means.

Dietary Cholesterol Intake Is Associated With Progression of Liver Disease in Patients With Chronic Hepatitis C: Analysis of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial.

After adjustments for age, sex, race, presence of cirrhosis, body mass index, treatment with peginterferon, lifetime alcohol consumption, smoking, health status, and coffee and macronutrient intake, each higher quartile of cholesterol intake was associated with a 46% increase in the risk of clinical or histologic progression (adjusted hazard ratio [AHR], 1.46; 95% confidence interval [CI], 1.13-1.87; P for the trend = .004). Compared with patients in the lowest quartile of cholesterol intake (32-152 mg/day), those in the 3rd (224-310 mg/day; AHR, 2.83; 95% CI, 1.45-5.51) and 4th quartiles (>310 mg/day; AHR, 2.74; 95% CI, 1.22-6.16) had significantly increased risk of disease progression.


The first thing I'm noticing is a poor dose-response relationship: the AHR from the highest quartile is slightly less than from the 3rd quartile. And the second quartile isn't available for comparison. But I'm prepared to believe for now that this effect can plateau. The second thing I notice is the number of adjustments for confounders, and no mention of the unadjusted results in the abstract. If the authors are coming from a position of prejudice (say they're vegans or similar plant-based zealots), this is where things will get tricky, But the correlation is so high I think we should give them the benefit of the doubt for now.
One confounder which is not mentioned is that individuals with the lowest cholesterol intake (it's quite hard to achieve these levels) were probably health-conscious individuals who also avoided processed food, ate plenty of fibrous vegetables, and were more likely to take vitamin, mineral and antioxidant supplements.
And another factor, one that shifts this from the ordinary, is the immune activation of long-term interferon treatment. They have adjusted for this, but the treatment may apply to all subjects, and the adjustment may be for duration, dose, numbers of treatments (correction: the HALT-C trial included a placebo arm).
Cholesterol is a nutrient, not a food. It's also a nutrient that can be damaged in the processing and preparation of food. Hopefully there will be tables in the full-text that detail the types of food that were used to calculate cholesterol consumption. The paper was published in the USA, so we can speculate about the ways cholesterol will get into the diet. From the cholesterol food charts we see that egg yolks, liver, butter, and crustaceans are high in cholesterol. Other common foods like meats and milk are lower but may be consumed in higher quantities. From this data (table 1) we see that pork can be rich in cholesterol. Pork offal used in sausages and processed meats must be especially so.
Americans do not eat large amounts of butter these days on a per capita basis, nor do they eat much seafood. Egg yolks are perhaps most likely to be consumed in baked goods and mayonnaise, perhaps even powdered eggs. What will also be consumed on a daily basis is meat, pork, chicken skin, and processed meat products, and also flavoured milk, whipped cream and other dairy products.
Is there any food on this list that already has a strong association with cirrhosis?
Pork does. The consumption of pork, and especially pork offal, is strongly associated with alcoholic cirrhosis across countries and counties, and in this "clinical microcosm" study.


Alcohol Clin Exp Res. 1998 Nov;22(8):1803-5.

Effect of the type of beverage and meat consumed by alcoholics with alcoholic liver disease.

Bode C, Bode JC, Erhardt JG, French BA, French SW.

Source

Institut für Biologische Chemie and Ernährungswissenschaft, F.B., Ernährungs Physiologie, Universität Hohenheim, Stuttgart, Germany.

Abstract

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.

There is also a correlation between pork and hepatocellular cancer which is quite strikingly independent of alcohol consumption in table 1 of this PDF.


I will not go into the pork data in detail because Paul Jaminet has already done so, in a series of 3 articles beginning here.
"Pork consumption has a strong epidemiological association with cirrhosis of the liver. Startlingly, pork may be even more strongly associated with alcoholic cirrhosis than alcohol itself!
The evidence was summarized by Francis Bridges in a recent (2009) paper [1], building on earlier work by Nanji and French [2]. A relation between pork consumption and cirrhosis of the liver is apparent across countries and has been consistently maintained for at least 40 years."

I'm not certain that the explanation Paul prefers (hepatitis E) completely explains the correlation, I still consider this a mystery for the ages. I did come across a possible explanation today which, though speculative, appeals to me.

Yersinia enterocolitica is a common bacterial contaminant of pork, especially ground pork, which is destroyed by cooking.
("Yersiniae are usually transmitted to humans by insufficiently cooked pork or contaminated water.")
It causes a nasty but self-limiting gastrointestinal syndrome, and can migrate to the liver, causing abscesses. But the most intriguing thing is a link between y. enterocolitica and arthritis. ("
Y. enterocolitica infections are sometimes followed by chronic inflammatory diseases such as arthritis."). Or fibrosis? Arthritis is a disease with a great deal in common with hepatic fibrosis, it involves similar inflammatory pathways and cellular processes and the same anti-inflammatory compounds are useful in both conditions. What if cirrhosis is promoted, not necessarily by infection with y. enterocolitica, but by exposure to the killed bacteria in cooked meat? In a leaky gut scenario (and IBO is also associated with cirrhosis), LPS that is present in the meat (or an exotoxin, or antigen, or YopP) finds its way to the liver and much the same immune reaction that causes arthritis eventuates there. Well it's a theory, and I really mention it as an example of the kind of thing that might be going on.

Stop Press: yersinia 
enterocolitica YOP antibodies are found in 20-25% of population, with higher incidence in autoimmune thyroiditis. YE is found in ascitic fluid of cirrhotics, especially alcoholic cirrhosis. Persistent asymptomatic YE infection, with potential for post infection autoimmune sequelae, seems to be relatively common.


Interestingly, dietary cholesterol (and saturated fat) are actually associated with protection from alcoholic cirrhosis, so it doesn't seem to be the cholesterol in the pork per se that makes it problematic.
So far, cholesterol might be harmful in the presence of fatty liver and choline deficiency, or it might be a marker for the harmful food pork. There is also the question of oxidized cholesterol. Cholesterol in food is oxidized by long cooking, drying, or high temperatures. You don't want the cholesterol in your bloodstream to become oxidized, this is a risk factor for atherosclerosis, so you probably want to keep that in your food fresh too (I find the science around this a little fuzzy, but why not). With eggs and butter, this is easy as very little cooking is needed; with meat it is harder (especially given the presence of pathogens). Slow cooking at low temperatures is probably the way to go, and especially boiling in water - stews and soups - where temperature is limited by the evaporation of the water as it heats.

I eat about 2 eggs a day, plenty of butter. I rarely eat offal, and it's either lamb kidneys or chicken liver, eaten instead of eggs. Maybe once a week. My cholesterol intake is definitely in the upper quartiles (and probably always has been, at least when I've been healthy enough to eat well). I also have occasional low-cholesterol, higher carbohydrate days when I will eat smaller amounts of sushi or stir-fry instead of my usual food. I figure this helps my gall bladder flush any extra, unwanted cholesterol it's holding, because we can't necessarily expect the enterohepatic circulation to work perfectly all the time. I eat bacon (which seems to be the least problematic form of pork immunologically) because it is so damn convenient and digestible, and probably have pork chop or mince once a week. I avoid most sausages, and all other processed meats. If my liver histology ever shifted in the direction of fibrosis (fibroscan still shows "mild scarring" after many decades of chronic self-abuse and HCV infection, some years more enjoyable than others), I would cut pork products completely as my first option. I would hate to move from eating butter to depending on some processed empty-calorie food like coconut oil. Butter has a cholesterol/choline ratio of 10:1, whereas egg yolk and chicken liver have a ratio of 2:1. Nuts, legumes and leafy vegetables are also supplying smaller amounts of choline. Cirrhosis is, almost always, a sequel to fatty liver disease, and a diet high in choline and saturated fat and low in carbohydrate and polyunsaturated fat will reverse fatty liver disease. I'm going to take a watching brief on this issue. I might consult this doctor:





Wednesday 19 June 2013

It Begins With Butter

The world at large will never be convinced of the benefits of low-carbohydrate diets until the still-vilified "saturated fat" is fully acquitted of the charges falsely laid in the courts of public opinion. Butter is the poster child for the defendant saturated fat, and also the most nutritious and beneficial of the all-fat foods. So any campaign to vindicate SaFAs should begin with butter.
If anyone needs reminding why it is essential that very low carb diets enter the medical mainstream today rather than tomorrow, I recommend Toxic's post on the subject. This is incendiary stuff, and if it doesn't make you feel like fire-bombing a bakery you have no soul.Churn, butter; Henderson & Pollard Ltd; [?]; CT78.743
(Minimal processing is required - you can make butter from cream at home with a jam jar and a marble)

A few weeks or months back I linked to the two studies by Mozaffarian et al. showing a protective association between dairy fat and diabetes (2010 and 2013). I pointed out that these observational studies used a more reliable measurement than the food frequency questionnaire, and that the correlation was of an order of magnitude (0.38 and 0.52) significant enough to be meaningful in the presence of plausible mechanisms. I know that some bloggers tend to completely reject dietary epidemiology, understandably given the mistaken weight given to the weakest correlations by prejudiced scientists in the media, but strong correlations imply causation, and will constitute part of the proof if causation is considered proven. Professor Feinman has written an excellent guide for the perplexed on the value of epidemiological studies in the scientific tradition, which I recommend to anyone confused about the issue.

Back when I was really sick with hepatitis and food allergies and so on, I thought I didn't tolerate fat so well. Fatty foods like icecream or creamy desserts made me throw up, and given the advice one heard, and still hears, the fat seemed the obvious culprit. But I could always eat butter without any problems, and I found it interesting that this fat, which I knew to be highly saturated, should never make me ill, indeed seemed to make me feel better. But still I took seriously, and to my shame repeated, that pernicious meme about saturated fats being bad and vegetable oils beneficial. It's called cognitive dissonance. Until one day in a spirit of inquiry - and thank God for the internet - I googled "health benefits of saturated fats", came across Mary Enig's writing on the Weston A. Price website, checked out the references, and came away a new man.

What is the fat in butter? 
It's the fat produced from a 100% plant-based, high-fibre diet by an animal actually designed to eat one. It's what cellulose would become in our bodies if we (or rather our microbiota) could metabolise cellulose, plus the products of other fibres, starches and sugars in the grass, silage, or other feeds, and any fatty acids therein. One of these products of fermentation is butyric acid, incorprated in triglycerides as butyrate; butyrate makes up 3-4% of butter and is also formed in the human gut when dietary fibre is fermented by the right bacteria. Most of the benefits of fibre in the diet seem to relate to the formation of butyrate, and if the bacterial species present are those that instead prefer to generate D-lactate, or high levels of propionate, the results will not be beneficial - see the section "D-lactic and propionic acid - a cautionary tale" half-way down this probiotic review.

(Sheep's milk is higher in butyrate and MCTs than cow's milk)

A popular probiotic in Japan is clostridium butyricum, which generates high levels of butyrate from dietary fibre. It turns out that these probiotics, or the butyrate derived from them, protect the liver from cirrhosis and cancer in the rat model of fatty liver disease (a diet deficient in choline and methionine - eat your eggs folks! Another demonized food that can actually save your life. In Colin T. Cambell's contentious China Study, the raw data shows a significant liver-protective effect of egg consumption). This study is a treat, full of photos and easy-to-understand graphics. It shows that even in the choline-methionine deficient rat (a huge metabolic barrier to surmount) the progression of cirrhosis and cancer is significantly slowed by butyrate (NaB).

Pharmacological studies and siRNA knockdown experiments showed that NaB-mediated AMPK activation induced the phosphorylation and nuclear translocation of Sirtuin 1, leading to the increased assembly of mammalian TOR complex 2 and phosphorylation of AKT at Ser473 and subsequent induction of Nrf2 expression and activation. These favorable changes caused an obvious decrease in hepatic fibrous deposition, GST-P-positive foci development, and hepatocarcinogenesis.

100 grams of butter, which would be about 1/3 of a day's calories, will supply 3-4 grams of butyrate and this is (roughly) as much as 6-8 grams of dietary fibre will supply under perfect conditions. The RDA says that foods that contain more than 6g fibre per 100g are considered high fibre foods, which means that butter is, in effect, a high fibre food, one where there is no risk of the fibre going to feed the wrong bacteria - it's all good. Cook some greens or other fibrous vegetables with your butter if you like, it helps to keep it on your knife, as when eating peas with honey.

(Camel's milk is the most hepatoprotective milk there is)

Here's an interesting human study showing that fat is the most important nutrient for people recovering from hepatocellular cancer (PDF). It's been couched in some technical oncologist or biophysics jargon that is mildly impenetrable, but what I get from it is this: people with cirrhosis do worse if they don't get enough energy (this is a universal finding - non-alcohol calories protect against cirrhosis progression). They tend to undereat protein, but the deficiency that has most impact on cancer recovery is fat. And the reason for this is that the metabolically damaged cirrhotic liver cannot derive energy from carbohydrate and protein with the same efficiency that it can generate ATP from fat. I can think of two reasons; a damaged liver has difficulty synthesizing co-enzymes from vitamin precursors, and the generation of ATP from carbohydrate and protein requires more variety of co-enzymes to be synthesized, and more enzymes, than the relatively simple, repetitive process of fatty acid beta-oxidation. The other reason will be familiar to regular readers of Hyperlipid; if the mitochondrial damage is mainly at Complex I, as is almost always the case for some reason, this will impede the generation of ATP from glucose (more NADH, less FADH2 generated, complex 1 handles the NADH) more than it impedes generation of ATP from fat (more FADH2 relative to NADH).
Fat, therefore, is easy on the liver, and saturated fat the easiest of all, because the simplest to metabolize. I've shown in earlier posts how saturated (and monounsaturated) fats protect the liver because of their inherent stability compared to polyunsaturated fats, passively supporting the liver's antioxidant defenses. Butter also contains fats as MCTs, up to 15%, less than coconut oil, it's a source of vitamins A, D, E, and K2 as well as carotenoids, cholesterol and CLA. I'm sure there's another post in all this, but I've written more than enough already.



Sunday 16 June 2013

On What I Eat These Days

"I forget most of what I have read, just as I do most of what I have eaten, but I know that both contribute no less to the conservation of my mind and my body on that account." - Georg Christop Lichtenberg on food frequency questionnaires.

I've procrastinated about this ever since Peter Hyperlipid posted his own classic eating update a while back, trying to contextualize what purpose a similar post of my own might serve. Ah-Ha! I see. OK then.
Basically, it's good to know these things can be done, are being done, and the reasons for certain decisions are probably worth revisiting.

Music by Mink - a lost treasure from 1996, "Your Bad Example".


Wake up - too early, give a brother some rest, my start is 6am these days which means coffee. Strong with cream and maybe if it's too strong a little soft brown sugar but, like, 1-2g, which is plenty sweet if you eat low carb, yet not enough to contribute to the world's fructose problem. Might have 2 or 3 coffees like this in the day (almost all without sugar). If it's instant coffee I'll stick a teabag in it because - I should have taken out a patent - this makes instant coffee taste like fresh coffee. Yup, I'm a wild and crazy guy, livin' on the edge now.

Coffee, as any fule kno, has powers to protect the liver in every study you can think of, and enhances the response to combination therapy in Hep C. Nice work if you can get it, as a poor liver function can slow caffeine metabolism and make you intolerant of coffee. So a little chicken-and-egg but still, there are solid biochemical reasons why both caffeine and coffee polyphenols of the caffeic acid family ought to inhibit fibrosis etc. (for example, caffeine blocks adenosine receptors, adenosine released from damaged cells serves as a chemoattractant "stop" signal for hepatic stellate cells, these cells remodel collagen matrix, caffeine is switching off their GPS. Caffeic acid phenethyl ester, CAPE, which you will also find in propolis and which is a normal metabolite of other dietary polyphenols, inhibits HCV replication. And so on.)

Other drinks I might enjoy, because I don't drink coffee after the early afternoon, include well water, green tea, black tea, red bush tea (aspalanthus, rooibos) or hibiscus flower. 


Breakfast I will try to have at 10am. I used to be stricter about food-window IF but now that my appetite is tamed I'm more concerned with getting sufficient energy so will eat outside of opening hours if I feel hungry. And if I'm going out for the day I have to eat early anyway. Breakfast is fairly consistent:
3 rashers bacon (chopped small), or occasionally most of a tin of sardines (the dog gets one) or a few kidneys or a chicken liver or two. Fried slowly in a tablespoon of beef and lamb dripping (AKA tallow). This takes care of excess PUFA in the bacon, as I add one large tomato, chopped (for the potassium and carotenoids), a tablespoon of butter (or two or more if I need extra energy), a teaspoon of crushed garlic, 2 (or 3) egg yolks, a bit of any gelatine broth I have lying around, spice and salt if needed. (Note; I use various pre-mixed Indian spice mixes, masalas. I only buy masalas that contain salt - chat - as an ingredient, as this shows attention has been paid to creating a rounded flavour). So any linoleic acid in the bacon or yolks has been diluted by the more saturated fats of the dripping and butter and shouldn't matter in the greater scheme of things.

Snacks - might or might not want these in the afternoon, which might be 25g dark chocolate, or a handful of almonds, 4 Brazil nuts for the selenium, or some cold meat left over from the night before. Probably a little fruit too; at the moment, that's mandarins, kiwifruit, persimmons. Used to eat cheese but I'm a bit allergic so trying to quit. If it's a higher-carb day - or I feel like it - I'll have a banana.

Dinner (served around 6pm): some meat (could be lamb shoulder chop, if it's chicken I'll stuff it with bacon, rolled oats, butter, sage, onions and fish sauce to up the SFA content). Or could be chicken or fish cooked in coconut cream. Or beef shin bone slowly cooked in a stew with one potato, carrots, onions.
But assuming it's the lamb chops, then a lower-carb vege good for fat-soaking will be roasted with them. Pumpkin, sweet potato, oca yam, whole garlic. Roasted Brussels sprouts are pretty special IMO. Any greens - leek, Chinese cabbage, spinach - will be comfited in butter (fried slowly with lots of butter till it goes soft). Boiled carrots, steamed green beans, mashed parsnip with cream, roasted beetroot are optional but welcome. I probably eat about 200g meat, which supplies about 40-50g protein. I prefer ruminant fat, so if the meat is chicken or pork I'll find a way to include more butter or dripping in the veges. I'm not against olive oil but find I have fewer occasions to eat it.


I'll have a cup of black tea after dinner because of some superstition about iron absorption, though I tend to agree with G. C. Lichtenberg, the best thing you can add to a meal is to remove drinking from the experience.

Dessert might be 2 teaspoons Bourneville cocoa mixed to a paste with cream and 1-2g soft brown sugar. A mousse of sorts I think. Occasionally mix up some kelp powder, spirulina powder, and olive oil to a paste and eat for iodine fix. Not pleasant but miles better than iodine deficiency, which will seriously mess you up. I also use the iodised table salt. I wish someone would add the iodine supplement to unprocessed sea salt.

Calories? I dunno. One day I sort of counted and it came to 1,800, so since then I've tried to stop undereating. Carbs? Probably 50g, not often more than 100g. But all starchy carbs are eaten at the evening meal, and with plenty of fat, so the GI and insulin rise is limited. And I do notice, over time, that this has left me feeling healthier and more energetic in the evenings. I try to stay out of glycogen-depleting ketosis but well below the supposed daily requirement of 150g glucose. Actually I would find it hard to eat 150 carb grams in a day with this diet. I don't often eat potatoes or rice, and I'm sceptical that resistant starch is a type of fibre I need. I do occasionally eat small amounts of oats at the moment. I figure that my Scottish genes - and my years of abstaining from wheat and rye - are enabling me to do this with seeming impunity.

I don't usually exercise for the sake of exercising, but I do run or jump or climb or whatever because I feel like it sometimes. Walking up big hills or small mountains is probably the most energetic thing I do, and swimming in the summer. My house is up a steep drive and a few flights of steps and I run up those rather than walk the boring slow way. Instinctive exercise, like instinctive eating, is what works best for me; attempts to develop my strength capacity tend to result in avoidable injuries, and it seems to be developing satisfactorily anyway.


Supplements - vitamin D and K2, magnesium 150-300mg, vitamin C 1g, occasional probiotics, very occasional low-dose multivitamin. I'd take selenium 100-150mcg if I didn't have Brazil nuts and would supplement zinc if I could find a cheap one with no B6.

So what we have here is Atkins-type macronutrient tinkering, tweaked for the effect on microbiota. Which is like "Phase 2" of any long-term diet plan (see Art Ayer's "Cooling Inflammation" link at the right).
So what do I make of the fact that high-fat diets can produce unwanted LPS elevations in rats and humans eating their respectively standard rat and human chows?


The quality of fats is important. Extrapolations from rodent diets where fats are 30% PUFA, are all extrinsic fats, carbohydrate is still a major part of energy as pure sugar and starch, and types and amounts of fibre are limited are only relevant to similar human diets; these rat diets often resemble cheesecake recipes.
My belief is that a high-fat diet (butter, fish, eggs for cholesterol and choline) can be used to restrict bacterial overgrowth (via higher levels of bile and stomach acid) and set the scene for the right fibre and probiotics to work. Further, butter is a good source of butyrate (about 3-4%), which means 100g butter contributes about as much butyrate as 6-8g dietary fibre on a good day without the risk of a non-specific prebiotic effect. My strategy is to cook whenever possible fibrous vegetables (pumpkin, greens, sweet potato, tomato, parsnip) with butter (as you will find in French quisine) which seems to work well.


Music - Mascagni, the "octopus aria" (Aria della poivra) from Iris.