Does pork consumption cause cirrhosis? Perhaps, if people become obese from eating pork

The idea that pork consumption may cause cirrhosis has been around for a while. A fairly widely cited 1985 study by Nanji and French () provides one of the strongest indictments of pork: “In countries with low alcohol consumption, no correlation was obtained between alcohol consumption and cirrhosis. However, a significant correlation was obtained between cirrhosis and pork.”

Recently Paul Jaminet wrote a blog post on the possible link between pork consumption and cirrhosis (). Paul should be commended for bringing this topic to the fore, as the implications are far-reaching and very serious. One of the key studies mentioned in Paul’s post is a 2009 article by Bridges (), from which the graphs below were taken.

The graphs above show a correlation between cirrhosis and alcohol consumption of 0.71, and a correlation between cirrhosis and pork consumption of 0.83. That is, the correlation between cirrhosis and pork consumption is the stronger of the two! Combining this with the Nanji and French study, we have evidence that: (a) in countries with low alcohol consumption we can find a significant correlation between cirrhosis and pork consumption; and (b) in countries where both alcohol and pork are consumed, pork consumption has the strongest correlation with cirrhosis.

Do we need anything else to ban pork from our diets? Yes, we do, as there is more to this story.

Clearly alcohol and pork consumption are correlated as well, as we can see from the graphs above. That is, countries where alcohol is consumed more heavily also tend to have higher levels of pork consumption. If alcohol and pork consumption are correlated, then a multivariate analysis of their effects should be conducted, as one of the hypothesized effects (of alcohol or pork) on cirrhosis may even disappear after controlling for the other effect.

I created a dataset, as best as I could, based on the graphs from the Bridges article. (I could not get the data online.) I then entered it into WarpPLS (). I wanted to run a moderating effect analysis, which is a form of nonlinear multivariate analysis. This is important, because the association between alcohol consumption and disease in general is well known to be nonlinear.

In fact, the relationship between alcohol consumption and disease is often used as a classic example of hormesis (), and its characteristic J-curve shape. Since correlation is a measure of linear association, the lower correlation between alcohol consumption and cirrhosis, when compared with pork consumption, may be just a “mirage of linearity”. In multivariate analyses, this mirage of linearity may lead to what are known as type I and II errors, at the same time ().

I should note that the Bridges study did something akin to a moderating effect analysis; through an analysis of the interaction between alcohol and pork consumption. However, in that analysis the values of the variables that were multiplied to create a “dummy” interaction variable were on their original scales, which can be a major source of bias. A more advisable way to conduct an interaction effect analysis is to first make the variables dimensionless, by standardizing them, and then creating a dummy interaction variable as a product of the two variables. That is what WarpPLS does for moderating effects’ estimation.

One more detour, leading to an important implication, and then we will get to the results. In a 1988 article, Jeanneret and colleagues show evidence of a strong and possibly causal association between alcohol consumption and protein-rich diets (). One possible implication of this is that in countries where pork is a dietary staple, like Denmark and Germany, alcohol consumption should be strongly and causally associated with pork consumption. (I guess Anthony Bordain would agree with this eh?)

Below are the results of a multivariate analysis on a model that incorporates the above implication, by including a link between alcohol and pork consumption. The model also explores the role of pork consumption as a moderator of the relationship between alcohol and cirrhosis, as well as the direct effect of pork consumption on cirrhosis. Finally, the total effects of alcohol and pork consumption on cirrhosis are also investigated; they are shown on the left.

The total effects are both statistically significant, with the total effect of alcohol consumption being 94 percent stronger than the total effect of pork consumption on cirrhosis. Looking at the model, alcohol consumption is strongly associated with pork consumption (which is consistent with Jeanneret and colleagues’s study). Alcohol consumption is also strongly associated with cirrhosis, through a direct effect; much more so than pork. Finally, pork consumption seems to strengthen the relationship between alcohol consumption and cirrhosis (the moderating effect).

As we can see the relationship between pork consumption and cirrhosis is still there, in moderating and direct effects, even though it seems to be a lot weaker than that between alcohol consumption and cirrhosis. Why does pork seem to influence cirrhosis at all in this dataset?

Well, there is another factor that is strongly associated with cirrhosis, and that is obesity (). In fact, obesity is associated with just about any major disease, including various types of cancer ().

And in countries where pork is a dietary staple, isn’t it reasonable to assume that pork consumption will play a role in obesity? Often folks who consume a lot of addictive industrial foods (e.g., bread, candy, regular sodas) also eat plenty of foods with saturated fat; and the latter end up showing up in disease statistics, misleadingly supporting the lipid hypothesis. The phenomenon involving pork and cirrhosis may well be similar.

But you may find the above results and argument not convincing enough. Maybe you want to see some evidence that pork is actually good for one’s health. The results above suggest that it may not be bad at all, if you buy into the obesity angle, but not that it can be good.

So I downloaded the most recent data from Nationmaster.com () on the following variables: pork consumption, alcohol consumption, and life expectancy. The list of countries was a bit larger than and different from that in the Bridges study; the following countries were included: Australia, Brazil, Canada, China, Denmark, France, Germany, Hong Kong, Hungary, Japan, Mexico, Poland, Russia, Singapore, Spain, Sweden, United Kingdom, and United States. Below are the results of a simple multivariate analysis with WarpPLS.

As with the Bridges dataset, there is a strong multivariate association between alcohol and pork consumption (0.43). The multivariate association between alcohol consumption and life expectancy is negative (-0.14). The multivariate association between pork consumption and life expectancy is positive (0.36). Neither association is statistically significant, although the association involving pork consumption gets close to significance with a P=0.11 (a confidence level of 89 percent; calculated through jackknifing, a nonparametric technique). The graphs show the plots for the associations and the best-fitting lines; the blue dashed arrows indicate the multivariate associations to which the graphs refer. So, in this second dataset from Nationmaster.com, the more pork is consumed in a country, the longer is the life expectancy in that country.

In other words, for each 1 standard deviation variation in pork consumption, there is a 0.36 standard deviation variation in life expectancy, after we control for alcohol consumption. The standard deviation for pork consumption is 36.281 lbs/person/year, or 45.087 g/person/day; for life expectancy, it is 4.677 years. Working the numbers a bit more, the results above suggest that each extra gram of pork consumed per person per day is associated with approximately 13 additional days of overall life expectancy in a country! This is calculated as: 4.677/45.087*0.36*365 = 13.630.

Does this prove that eating pork will make you live longer? No single study will “prove” something like that. Pork consumption is also likely a marker for wealth in a country; and wealth is strongly and positively associated with life expectancy at the country level. Moreover, when you aggregate dietary and disease incidence data by country, often the statistical effects are caused by those people in the dietary extremes (e.g., alcohol abuse, not moderate consumption). Finally, if people avoid death from certain diseases, they will die in higher quantities from other diseases, which may bias statistical results toward what may look like a higher incidence of those other diseases.

What the results summarized in this post do suggest is that pork consumption may not be a problem at all, unless you become obese from eating it. How do you get obese from eating pork? Eating it together with industrial foods that are addictive would probably help.

What Causes Insulin Resistance? Part IV

So far, we've explored three interlinked causes of insulin resistance: cellular energy excess, inflammation, and insulin resistance in the brain.  In this post, I'll explore the effects on micronutrient status on insulin sensitivity.

Micronutrient Status

There is a large body of literature on the effects of nutrient intake/status on insulin action, and it's not my field, so I don't intend this to be a comprehensive post.  My intention is simply to demonstrate that it's important, and highlight a few major factors I'm aware of.

Read more »

Oltipraz

Oltipraz is a drug that was originally used to treat intestinal worms. It was later found to prevent a broad variety of cancers (1). This was attributed to its ability to upregulate cellular detoxification and repair mechanisms.

Researchers eventually discovered that oltipraz acts by activating Nrf2, the same transcription factor activated by ionizing radiation and polyphenols (2, 3, 4). Nrf2 activation mounts a broad cellular protective response that appears to reduce the risk of multiple health problems.

A recent paper in Diabetologia illustrates this (5). Investigators put mice on a long-term refined high-fat diet, with or without oltipraz. These carefully crafted diets are very unhealthy indeed, and when fed to rodents they rapidly induce fat gain and something that looks similar to human metabolic syndrome (insulin resistance, abdominal adiposity, blood lipid disturbances). Adding oltipraz to the diet prevented the fat gain, insulin resistance and inflammatory changes that occurred in the refined high-fat diet group.

The difference in fasting insulin was remarkable. The mice taking oltipraz had 1/7 the fasting insulin of the refined high-fat diet comparison group, and 1/3 the fasting insulin of the low-fat comparison group! Yet their glucose tolerance was normal, indicating that they were not low on insulin due to pancreatic damage. The low-fat diet they used in this study was also refined, which is why the two control groups (high-fat and low-fat) didn't diverge more in body fatness and other parameters. If they had used a group fed unrefined rodent chow as the comparator, the differences between groups would have been larger.

This shows that in addition to preventing cancer, Nrf2 activation can attenuate the metabolic damage caused by an unhealthy diet in rodents. Oltipraz illustrates the power of the cellular hormesis response. We can exploit this pathway naturally using polyphenols and other chemicals found in whole plant foods.

Polyphenols, Hormesis and Disease: Part II

In the last post, I explained that the body treats polyphenols as potentially harmful foreign chemicals, or "xenobiotics". How can we reconcile this with the growing evidence that at least a subset of polyphenols have health benefits?

Clues from Ionizing Radiation

One of the more curious things that has been reported in the scientific literature is that although high-dose ionizing radiation (such as X-rays) is clearly harmful, leading to cancer, premature aging and other problems, under some conditions low-dose ionizing radiation can actually decrease cancer risk and increase resistance to other stressors (1, 2, 3, 4, 5). It does so by triggering a protective cellular response, increasing cellular defenses out of proportion to the minor threat posed by the radiation itself. The ability of mild stressors to increase stress resistance is called "hormesis." Exercise is a common example. I've written about this phenomenon in the past (6).

The Case of Resveratrol

Resveratrol is perhaps the most widely known polyphenol, available in supplement stores nationwide. It's seen a lot of hype, being hailed as a "calorie restriction mimetic" and the reason for the "French paradox."* But there is quite a large body of evidence suggesting that resveratrol functions in the same manner as low-dose ionizing radiation and other bioactive polyphenols: by acting as a mild toxin that triggers a hormetic response (7). Just as in the case of radiation, high doses of resveratrol are harmful rather than helpful. This has obvious implications for the supplementation of resveratrol and other polyphenols. A recent review article on polyphenols stated that while dietary polyphenols may be protective, "high-dose fortified foods or dietary supplements are of unproven efficacy and possibly harmful" (8).

The Cellular Response to Oxidants

Although it may not be obvious, radiation and polyphenols activate a cellular response that is similar in many ways. Both activate the transcription factor Nrf2, which activates genes that are involved in detoxification of chemicals and antioxidant defense**(9, 10, 11, 12). This is thought to be due to the fact that polyphenols, just like radiation, may temporarily increase the level of oxidative stress inside cells. Here's a quote from the polyphenol review article quoted above (13):

We have found that [polyphenols] are potentially far more than 'just antioxidants', but that they are probably insignificant players as 'conventional' antioxidants. They appear, under most circumstances, to be just the opposite, i.e. prooxidants, that nevertheless appear to contribute strongly to protection from oxidative stress by inducing cellular endogenous enzymic protective mechanisms. They appear to be able to regulate not only antioxidant gene transcription but also numerous aspects of intracellular signaling cascades involved in the regulation of cell growth, inflammation and many other processes.

It's worth noting that this is essentially the opposite of what you'll hear on the evening news, that polyphenols are direct antioxidants. The scientific cutting edge has largely discarded that hypothesis, but the mainstream has not yet caught on.

Nrf2 is one of the main pathways by which polyphenols increase stress resistance and antioxidant defenses, including the key cellular antioxidant glutathione (14). Nrf2 activity is correlated with longevity across species (15). Inducing Nrf2 activity via polyphenols or by other means substantially reduces the risk of common lifestyle disorders in animal models, including cardiovascular disease, diabetes and cancer (16, 17, 18), although Nrf2 isn't necessarily the only mechanism. The human evidence is broadly consistent with the studies in animals, although not as well developed.

One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin (19). Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals (20, 21).

Chris Masterjohn first introduced me to Nrf2 and the idea that polyphenols act through hormesis. Chris studies the effects of green tea on health, which seem to be mediated by polyphenols.

A Second Mechanism

There is a place in the body where polyphenols are concentrated enough to be direct antioxidants: in the digestive tract after consuming polyphenol-rich foods. Digestion is a chemically harsh process that readily oxidizes ingested substances such as polyunsaturated fats (22). Oxidized fat is neither healthy when it's formed in the deep fryer, nor when it's formed in the digestive tract (23, 24). Eating polyphenol-rich foods effectively prevents these fats from being oxidized during digestion (25). One consequence of this appears to be better absorption and assimilation of the exceptionally fragile omega-3 polyunsaturated fatty acids (26).

What does it all Mean?

I think that overall, the evidence suggests that polyphenol-rich foods are healthy in moderation, and eating them on a regular basis is generally a good idea. Certain other plant chemicals, such as suforaphane found in cruciferous vegetables, and allicin found in garlic, exhibit similar effects and may also act by hormesis (27). Some of the best-studied polyphenol-rich foods are tea (particularly green tea), blueberries, extra-virgin olive oil, red wine, citrus fruits, hibiscus tea, soy, dark chocolate, coffee, turmeric and other herbs and spices, and a number of traditional medicinal herbs. A good rule of thumb is to "eat the rainbow", choosing foods with a variety of colors.

Supplementing with polyphenols and other plant chemicals in amounts that would not be achievable by eating food is probably not a good idea.


* The "paradox" whereby the French eat a diet rich in saturated fat, yet have a low heart attack risk compared to other affluent Western nations.

** Genes containing an antioxidant response element (ARE) in the promoter region. ARE is also sometimes called the electrophile response element (EpRE).

Hormesis

Why are we so soft today? Why is it that our ancestors were able to perform feats like killing bears and wooly mammoths in snow-swept grasslands? How do present-day tribesmen withstand days of ultra-cold temperatures in Northern Greenland and prolonged periods without water in scorching hot Kenyan deserts? Why is it that a century ago, children in the Swiss alps ran barefoot through ice-cold mountain streams on cold days, while now they get carpal tunnel syndrome playing video games? How did they do all this without succumbing to the chronic diseases that are so rampant today? I believe part of the answer lies in hormesis.

Hormesis is the process by which a mild or acute stressor increases resistance to other, more intense or chronic stressors. It can increase resistance to a variety of stresses, not only the one to which you are exposed.

It might sound like a foreign concept, but you're more familiar with it than you think. Exercise is a form of hormesis. It's a stress placed upon the body that increases resistance to a number of other stressors: physical exertion, cardiovascular disease, depression, diabetes, age-related cognitive decline, neurodegenerative disease, etc.

Intermittent fasting is one of the most promising forms of hormesis. It's consistent with the variable energy intake our hunter-gatherer ancestors probably experienced. As with some other forms of hormesis, it has broad-ranging effects on health and stress resistance. Alternate-day fasting, a version in which food is available for 24 hours ad libitum and then not available for the next 24 hours, increases mean lifespan in mice under some conditions without reducing calorie intake. It increases resistance to neurodegeneration, stroke, myocardial infarction, toxins, cancer and diabetes in rodents. It increases the expression of heat shock proteins and SIRT1, both implicated in general stress resistance. Basically, it makes them tougher all-around.

Although only a few studies have been performed in humans, IF looks promising for preventing or reversing diabetes, cardiovascular disease, overweight and possibly other health problems. It can also decrease fasting insulin and increase insulin sensitivity considerably. I fast for 24 hours, once a week. No calories, only water. It's not a form of caloric restriction, because I eat like horse the day after fasting. It's just a mild stressor that toughens my body to other stressors.

I also take cold showers. Here the scientific data are more sparse, but it has a long history of use as a form of "body hardening". I do it to increase my cold resistance by firing up my non-shivering thermogenesis. It seems to be working. It certainly wakes me up in the morning! Have you ever noticed how you can get into cold water and be surprisingly comfortable once you're used to it, even though you're practically naked and water is conducting heat away from your body 20 times faster than air would? That's probably your non-shivering thermogenesis kicking in.

There are probably many other ways to induce hormesis. Do any of you have techniques to share? By the way, hormesis is one of the central tenets of homeopathy. Solid principle, incorrect application. I'd be happy to sell anyone sugar pills for 50% less than his or her local homeopath is selling them. I promise mine are equally effective...

Soft living makes a soft body. Give it some controlled stress from time to time!


Thanks to Kirill Tropin for the CC photo.