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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.


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.


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


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:


Nigel Kinbrum said...

I've just had an urge to make pork belly strips w/sweet chilli sauce, covered in Tesco stir-fry veg mix and microwaved 'till tender. That cooks at <100°C.

It's 7:45am here :-/

George Henderson said...

It is worth noting that, for all the alcohol and pork consumed, the incidence of chronic hepatitis and gluten sensitivity, and the existence of hepatotoxic drugs, radiation and pollutants, cirrhosis is still a rare condition, 0.15% incidence in the USA, and mortality from hepatocellular cancer much rarer, at 3.2 per 100,000 in 2006.

Nigel Kinbrum said...

I had 3 fried eggs, instead.

Bill said...

Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis.

I have tons of histology slides from broken mouse livers - found loads of Crown-Like Structures but never thought to look for cholesterol crystals...

On another note, ACAT inhibitors really were a bad idea.

George Henderson said...

Allergy to pork:

Our results revealed that cooked and roasted pork meat retained allergenic epitopes capable of inducing IgE-mediated food allergy.

Bill, there seems to be a vicious cycle in NASH;
oxidised cholesterol stimulates fatty acid synthesis, the fatty acid accumulation (I suspect) increases cholesterol synthesis, and there is an increased rate of DNL from carbohydrate. The liver is the insulin clearing organ so we get hyperinsulinaemia. Also, clearing insulin may be a source of cysteine for hepatic glutathione. This is part of a pet theory, that hyperinsulinaemia and immune complexes can deprive cells - esp. hepatocytes and beta cells - of cysteine, depleting hepatic glutathione and eventually lowering insulin synthesis (which depends on both structural cysteine and reduced glutathione).
It has the advantage of being a very simple mechanical theory, the disadvantage that there's no supporting evidence beyond a certain superficial plausibility, and the fact that NAC relieves both pancreatitis and hepatitis.

ItsTheWooo said...

I imagine anything that can promote arthritis and inflammation would exacerbate progression of fibrosis of liver, yes. Interesting :D

I wonder if cholesterol isn't protective but more of a marker of a healthy functional liver? Liver cooks up cholesterol after all. The sat fat vs PUFA effect is probably def. real though.

Maybe moodiness I experience from some kinds of meat isn't necessarily related to amino acid sensitivity (glutamate) but it very well may relate to sensitivity to microbes. This easily explains the observation of poorly handled/old meat tending to be promoting of dysphoria. Kosher meat , or very fresh meat, or eggs, does not.

Inositol is implicated in fatty liver and inositol supplements are noted to resolve .

I have never observed much significant trouble with pork, although these days I eat pork fairly uncommonly except in form of processed/cured pork fat like pork chicarones or bacon or pepperoni.

George Henderson said...

Woo, persistent asymptomatic yersinia e. infection seems to be fairly common. If some people are more sensitive to its presence this may be due to the Black Death, Y. pestis, selecting for immmune sensitivity to generic yersinia proteins. Or not.

Effect of pathogens in meat should be more noticable from ground meat than whole.

I do think that lipid panels being diet-appropriate is a sign of liver function. In the case of HBV and HCV these depress hepatic cholesterol output for reasons connected with their life cycles.

In alcohol/PUFA fed rats, dietary cholesterol 1% protects against hepatic necrosis and immediate toxicity but increases fibrosis. It downregulates COX2 and LDL-R, good, but upregulates TGF-beta, bad.

In rats given intragastric ethanol and either corn or fish oil,
addition of cholesterol (1%) does not change the degree of
fatty infiltration but prevents hepatic necrosis and inflammation and enhances hepatic fibrosis. Cholesterol in this model
decreases the enhanced low-density lipoprotein receptor
message, eliminates messages for TNF-a and COX-2, and
decreases plasma and liver levels of thromboxane B2, and
products of lipid peroxidation, whereas it increases transforming growth factor-b message. The anti-inflammatory effects of
cholesterol are most likely related to a decreased uptake of
arachidonic acid caused by downregulation of the low density lipoprotein receptor and its decreased conversion to
eicosanoids via decreased COX-2 activity. Enhanced fibrosis
may be mediated by increased transforming growth factor-b

Bill said...

"pork may be even more strongly associated with alcoholic cirrhosis than alcohol"

For some reason my brain repeatedly fails to associate this with bacon, focusing only on pork tenderloins and the like :/

On another note, what's up with the coconut oil hate? I usually reserve phrases like "processed empty calorie food" for far more nefarious food-like products.

George Henderson said...

I listened to a radio program where an expert talked about making oil from coconuts, it's an industrial process. I mean to look into it more, hut things like deodorizing are important. Very few vitamins in the coconut oil but granted, SCFA and MCTs are valuable nutrients. Just wanted to put in a balance to the paleo idea that this oil is universally great and can be a major part of diet. Grated or pulped coconut flesh, frozen or in sealed packs, would be the more paleo version. I tend to use coconut cream rather than the oil.

Yes, curing bacon seems to make it less porky. The worst offender may be the pork liverwurst type of sausage.

George Henderson said...

I wrote to Dr Yu with the pork data, he replied to me. He thinks the data suggests a causative effect of cholesterol in the progression of HCV fibrosis and cirrhosis. This would be consistent with the TGF-beta activation seen in the rat model.

Note that all subjects in the HALT-C trial, including controls, were non-responders to, or relapsers after, interferon-alpha treatment. I would expect more autoimmune sensitivities in this group.

George Henderson said...

I am thinking Dr Yu may be right, and what his study indicates is the effect of cholesterol, in NAFLD due to diabetogenic diet plus diabetogenic virus, leading to NASH.
Cholesterol in a diabetogenic diet = trouble? I'll write this up soon.

Michal said...


Personally I think, that this is very flawed study based on questionnaires, overlooking many important confounding factors which may influence clinical and histological progression of liver disease in patients with hepatitis C, including virological factors (genotype), nutritional factors (type of fats, micronutrient and anitoxidant intakes), host factors (e.g. type of lipoproteins, ethnicity). Most importantly, prospective studies supports a role of low serum total and LDL-cholesterol and of oxidative stress as positive independent predictive factors of poor RVR in HCV patients. Coversely, high LDL- cholesterol and total cholesterol and lower triglycerides were were associated with higher rates of SVR. There is also significant amount of experimenatal and epidemiological evidence that omega-6 fatty acids increase progression of liver fibrosis.

More informations about hepatitis C and diet you can find on my FBP:

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