Monthly Archives: July 2011 - Page 3

Low Serum Cholesterol in Newborn Babies

Don Matesz, who has embraced low-fat and low-cholesterol dieting, recently stated that “I now consider anything over ~160 mg/dl [to be] excess serum cholesterol” and cited in his support the Cordain-Eaton claims that healthy hunter-gatherers had low serum cholesterol. Of course, we looked at that and found that healthy hunter-gatherers generally had serum cholesterol over 200 mg/dl and that hunter-gatherers with low serum cholesterol generally had high infectious burdens and short lifespans. See:

When Erik referenced our series and asked, “What do you think of the argument that low cholesterol in hunter gatherer populations stems from infections and parasites?”, Don replied:

Mean total blood cholesterol of healthy human neonates is about 72 mg/dl.

Is this due to infections and parasites?

In case this question was not merely rhetorical, let me answer: No.

But it’s an interesting biology question. Why do neonates have low serum cholesterol?

Neonates and Infants

The study that Don cited [1] looked at cord blood from neonates. Cord blood is blood that circulates on the fetal side of the placenta in utero. As soon as the baby is delivered, the cord is cut and blood ceases to circulate.

So the cord blood serum cholesterol of 70.3 mg/dl is really sampling fetal cholesterol – the blood of babies who have never eaten and never breathed.

The not eating part is relevant, because HDL is generated from the metabolism of chylomicrons created in the intestine when fat is eaten, and LDL is generated from VLDL particles that carry excess calories as triglycerides from the liver. So eating generates LDL and HDL. We might expect that LDL and HDL, and thus TC, levels will rise as soon as the neonate starts feeding.

We can check this out by looking at cholesterol levels in infants. The following data is from Japan [2], but any healthy population would give similar results:

Serum total cholesterol in infants, mg/dl, by feeding method

Infant Age Formula-fed Partially breastfed Breastfed
One month 117 142 163
Six months 140 162 194

Source: Tables 2 and 3, Isomura et al 2011.

The key data is in the rightmost column, the breastfed babies. By one month postpartum, TC is 163 mg/dl (“excess serum cholesterol” on Don’s view). By six months, it is 194 mg/dl.

Formula fed babies had a much smaller rise in TC.

To understand the pattern of this data, let’s look at three issues:

  • Why do formula-fed babies have lower TC than breastfed babies?
  • Why do neonates have low TC?
  • Why do breastfed babies end up with TC near 200 mg/dl?

Formula is a lipid-deficient food

Why do formula fed babies have lower serum cholesterol? One contributing factor may be a dietary lipid deficiency.

Human breast milk is rich in cholesterol. One study found that the cholesterol content of human breast milk follows a diurnal rhythm with a low of 140 mg/L during sleeping hours and early morning, and a high of 220 mg/L in the afternoon and evening. Other studies agree that human breast milk always has more than 100 mg/L cholesterol. Babies typically drink 750 mL/day, so a breastfed baby’s daily cholesterol intake is 100 to 200 mg.

Scaled by body weight, this would be the equivalent of 1.5 to 3 grams cholesterol per day for adults – approximately ten times the typical cholesterol intake of American adults.

Clearly, evolution thinks babies should get plenty of cholesterol.

But cholesterol levels in formula are much lower:

Since … infant formulas contain very little cholesterol (10 to 30 mg/L) (Huisman et al., 1996; Wong et al., 1993), it is not surprising that plasma cholesterol concentrations are higher in infants fed human milk than in formula-fed infants.

I guess the formula makers don’t consider cholesterol to be a desirable nutrient. This may be an extremely consequential mistake.

Low TC in Neonates May Have Evolved to Suppress Immunity

So why do neonates have a very low TC?

In addition to fat and cholesterol transport, LDL and HDL both have immune functions. Low serum cholesterol signifies a loss of these immune functions. Normal immune function is associated with TC around 200 mg/dl or higher.

But infants are well known to have suppressed immunity. This is important: if the fetus had an ability to generate antibodies and mount an immune response, it might generate immune attacks against the mother leading to miscarriage.

After birth, a baby’s immune system gradually matures:

A baby’s immune system is not fully developed until he/she is about six months-old. In the meantime, pregnant mothers pass immunoglobulin antibodies from their bloodstream, through the placenta, and to the fetus. These antibodies are an essential part of the fetus’s immune system. They identify and bind to harmful substances, such as bacteria, viruses, and fungi that enter the body. This triggers other immune cells to destroy the foreign substance….

Immediately after birth, the newborn has high levels of the mother’s antibodies in the bloodstream. Babies who are breastfed continue to receive antibodies via breast milk…. This is called passive immunity because the mother is “passing” her antibodies to her child. This helps prevent the baby from developing diseases and infections.

During the next several months, the antibodies passed from the mother to the infant steadily decrease. When healthy babies are about two to three months old, the immune system will start producing its own antibodies. During this time, the baby will experience the body’s natural low point of antibodies in the bloodstream. This is because the maternal antibodies have decreased, and young children, who are making antibodies for the first time, produce them at a much slower rate than adults.

Once healthy babies reach six months of age, their antibodies are produced at a normal rate.

LDL particles, by presenting pathogen toxins to macrophages which can then present them on MHC molecules, play an important role in the generation of antibodies. (See Blood Lipids and Infectious Disease, Part II, July 12, 2011.) Low LDL signifies a reduced ability to generate antibodies.

Low LDL is therefore highly desirable as long as the baby remains in the womb, and in fact LDL levels are very low in utero.

But persistent low LDL after birth is dangerous: it makes the infant vulnerable to infections. Likewise, HDL has important immune functions (see HDL and Immunity, April 12, 2011). So LDL and HDL gradually rise to normal physiological levels, finally reaching a TC of 200 mg/dl after 6 months in breastfed babies – precisely when the babies attain normal immune function.

If TC of 190 mg/dl or higher signifies normal immune function, then formula fed babies are still immune suppressed at 6 months. Extrapolating the rise in TC, partially breast fed babies might achieve normal immune function at 12 months and formula fed babies might not achieve normal immunity until age 24 months!

Immunity Matters for Infant Health

I don’t want to delve too deeply into this, but infants are vulnerable to infections – this is why infant mortality has always been high. It still is today, and 6 months of age is still the canonical age when the danger lessens:

Globally, approximately 4,000,000 children less than 6 months of age die each year at a rate of 450 deaths per hour. In addition, high hospitalization costs for infected infants are incurred in the United States with an annual estimated cost of $690,000,000.

Formula feeding definitely escalates the risk:

In the United States, more than 40% of all infant hospitalizations are attributable to infectious disease … Diarrhoeal diseases and digestive tract infections are the most common infectious diseases in infants….

Breast feeding has been shown to have a number of beneficial effects in infants, including protection against infectious and allergic diseases. [3]

In this study, 41% of formula-fed infants developed infections between ages 5 and 8 months. [3]

A study from Brazil [4] shows that breastfeeding makes a huge difference in infant mortality:

In a population-based case-control study of infant mortality in two urban areas of southern Brazil, the type of milk in an infant’s diet was found to be an important risk factor for deaths from diarrhoeal and respiratory infections. Compared with infants who were breast-fed with no milk supplements, and after adjusting for confounding variables, those completely weaned had 14.2 and 3.6 times the risk of death from diarrhoea and respiratory infections, respectively. Part-weaning was associated with corresponding relative risks (RR) of 4.2 and 1.6. [4]

Now, deficient serum cholesterol is not the sole factor accounting for higher mortality in formula fed babies. But it is a contributing factor.

Conclusion

If serum cholesterol is healthiest below 160 mg/dl, then formula fed babies have excellent blood lipids despite a high disease and mortality rate, but breastfed babies are already in trouble at age one month and are suffering a shocking dyslipidemia at age six months, despite excellent health.

I think that’s absurd. A more logical interpretation of the evidence is this.

Healthy babies achieve serum cholesterol levels around the adult norm of 200 mg/dl by age six months.

Serum cholesterol levels below 190 mg/dl or so indicate immune suppression and increased risk of infectious disease – whatever the age of the human in question. Formula fed babies are immune suppressed for an extended period – well beyond the six month period of a healthy breastfed baby.

There are multiple causes of low serum cholesterol. A high infectious burden is one; never having eaten is another; a lipid-deficient diet is a third. But there is no evidence I am aware of suggesting that low serum cholesterol is a desirable condition.

References

[1] Mishkel MA. Neonatal plasma lipids as measured in cord blood. Can Med Assoc J. 1974 Oct 19; 111(8):775-80. http://pmid.us/4370703.

[2] Isomura H et al. Type of milk feeding affects hematological parameters and serum lipid profile in Japanese infants. Pediatr Int. 2011 Mar 21. http://pmid.us/21418403.

[3] Picaud JC et al. Incidence of infectious diseases in infants fed follow-on formula containing synbiotics: an observational study. Acta Paediatr. 2010 Nov;99(11):1695-700. http://pmid.us/20560895.

[4] Victora CG et al. Evidence for protection by breast-feeding against infant deaths from infectious diseases in Brazil. Lancet. 1987 Aug 8;2(8554):319-22. http://pmid.us/2886775.

Blood Lipids and Infectious Disease, Part II

OK, after a diversion into hunter-gatherer lipid profiles I’m back on the original goal of this series: trying to understand why serum cholesterol is protective against infections — and considering whether or under what circumstances that knowledge should affect how we eat.

In part I (Blood Lipids and Infectious Disease, Part I, Jun 21, 2011), we learned that mortality from infectious disease is essentially zero as long as serum cholesterol remains in the physiologically normal range of 200 to 240 mg/dl, and rises precipitously as serum cholesterol falls below 180 mg/dl.

Why is that? In a previous post we found that HDL has important immune functions (HDL and Immunity, April 12, 2011). Today, we’ll look at the immune functions of lipoproteins more generally.

The Logic of Evolution and the Multiple Functions of Lipoproteins

In understanding why these particles have immune functions, it may be helpful to understand the thrust of evolution.

By the time of the Cambrian explosion 530 million years ago, organisms had similar numbers of genes to organisms today, and most of these genes must have been similar in sequence to their modern descendants. We know this because their descendant genes in nearly all modern species are “homologous” and share nucleotide sequences.

So for the last 500 million years, evolution has not been adding genes or even changing genes dramatically. It’s been tweaking a fairly stable genome. And the direction of the tweaking has been toward making the genes interact in a wider and more complex number of ways with the other genes.

The effect is to give every molecule in the body a diversity of functions. Possibly serum lipoprotein particles started out merely as transporters. But they developed new functions. The most important additional functions were roles in immunity.

Because these particles circulate in the blood, and pathogens have to transit the blood in order to cause tissue infections, blood is the natural location for the strongest defenses against pathogens. For hundreds of millions of years, every blood component will have been under selective pressure to develop immune functions.

It’s commonly said that the primary function of LDL and HDL is lipid transport. But this is too narrow a view. Since pathogens are the primary cause of disease, it may be the immune functions of LDL and HDL which account for their significance as biomarkers of health and disease.

The Immune Functions of Lipoproteins

Most of the following discussion will draw from a recent review, “Plasma lipoproteins are important components of the immune system” [1]. References from this paper will be listed in parentheses, eg (1).

Lipoproteins have been shown to:

  1. Prevent bacterial, viral, and parasitic infections.
  2. Detoxify pathogen “die-off” toxins and protect against pathogen toxin-induced tissue damage.
  3. Present pathogen “die-off” toxins to the immune system to trigger antibody formation.

Detoxification and Toxin Defense

When a pathogen dies, it typically fragments and releases compounds which are toxic to humans. Such “die-off” toxins include lipopolysaccharides (LPS) and lipooligosaccharides (LOS) from Gram-negative bacteria, lipoteichoic acid (LTA) from Gram-positive bacteria, fungal cell wall components, and so on.

During infection, the number of such circulating toxins can be vastly larger than the number of pathogens. Such toxins can do a great deal of harm, and often account for most of the ill effects of disease. Medical researchers studying the often-fatal condition of sepsis commonly induce nearly all the characteristics of sepsis in animals merely by injecting LPS.

VLDL, LDL, lipoprotein(a) and HDL can all detoxify LPS and LTA; HDL is the most potent (2, 4, 5). Injecting reconstituted HDL (rHDL) into humans relieves endotoxemia (6) and LPS-induced inflammation in cirrhosis patients (7). Both LDL and HDL detoxify E. coli LPS (35).

LDL binds and inactivates some toxins, including Staphylococcus aureus ?-toxin (8), Yersinia pestis topH6-Ag (30). (Methicillin-resistant S. aureus, or MRSA, is an increasing cause of death in hospitals, and last year claimed my next-door neighbor. See The FDA Is On The Side of the Microbes, Aug 11, 2010).

LDL probably works against many other toxins too, since rats with low LDL have higher mortality when infected, but the mortality can be lessened with injections of human LDL (9). Injections of LDL prevent lethality in Vibrio vulnificus infections of mice (34).

In mice with the LDL receptor knocked out, LDL concentrations in blood are higher and there is enhanced immunity to Klebsiella pneumoniae (27) and Salmonella typhimurium (29). If the gene for apoE, a protein found in IDL which upregulates VLDL levels, is knocked out, mice become more susceptible to infection, so it appears that apoE also has immune functions (28). Mice lacking apoE are susceptible to Listeria monocytogenes (32) and Mycobacterium tuberculosis (33).

Lipoproteins may be even more important against viruses. HDL has a broad antiviral activity (18-20), and can prevent many virus species including influenza and hepatitis C from entering cells. VLDL and LDL have specific activity against certain types of virus including togaviruses and rhabdoviruses (3). Trypanosoma brucei, the parasite that causes sleeping sickness, does not always cause disease in humans because a subspecies can be destroyed by a subfraction of HDL particles which include haptoglobin-related protein and apolipoprotein L-I (10).

The role of oxLDL

Evolution has a way of turning lemons into lemonade, and fragile molecules into sensors. In the book we discuss how the body uses fragile polyunsaturated fats as signaling molecules, exploiting their proclivity to oxidize. Something similar happens with LDL.

LDL particles are fragile and easily oxidized. The body uses them as a sensor of infections, and as signaling molecules that control the response to infections.

For instance, LPS (an endotoxin) induces neutrophils to adhere to endothelial cells, promoting vascular inflammation. LPS also oxidizes LDL, creating a compound called oxPAPC which inhibits neutrophil adhesion to endothelial cells, thereby limiting the inflammatory response (12). Minimally oxidized LDL detoxifies LPS (13).

OxLDL is taken in not by the LDL receptor, but by receptors on immune cells called macrophages. When macrophages take up oxLDL they upregulate their scavenger receptors (classes A and E) by which they phagocytose (eat) bacteria and clear endotoxins (39). It has been shown that infection causes an increase in oxidation of LDL and that the resulting oxLDL promotes phagocytosis by macrophages of the specific pathogens which oxidized the LDL (42).

This may explain why atherosclerotic lesions contain large amounts of bacterial and viral DNA. Macrophages in these lesions have been stimulated by oxLDL to scavenge bacteria and viruses from the blood.

OxLDL stimulates antibody formation, including antibodies against phosphorylcholine (PC), a compound found on a wide range of pathogens including bacteria, parasites, and fungi (45-49). Anti-PC antibodies help to prevent upper airway infections (50-53).

It is thought that oxidation of LDL is an important part of the host defense to infections. OxLDL inhibits cell entry of hepatitis C (59) and Plasmodium sporozite (60).

The role of Lp(a)

Lp(a) is essentially an LDL particle with an extra apo(a) molecule bound to the apoB100 molecule by a disulfide bridge.

Some insight into the immune functions of Lp(a) developed after considering the role of plasminogen. Many pathogens recruit human plasminogen and use it to penetrate tissue barriers, enabling them to invade tissue (70, 71, 72). For instance, group A streptococcus releases an enzyme called streptokinase that activates human plasminogen and promotes invasion (73). Lp(a) has anti-fibrinolytic activity and recruits plasminogen itself, reducing availability for pathogens. For instance, Lp(a) blocks streptokinase activity (75), inhibits Staphylococcus aureus activation of plasminogen.

Moreover, Lp(a) inhibits the inflammatory response to LPS. As there is great variation in Lp(a) levels among individuals (76), this may account for variability in inflammatory response to infections.

The Exception: Candida

HDL may promote fungal infections. A recent study found that infusion of reconstituted HDL enhances the growth of Candida (25).

LDL also seems to promote fungal infections. In LDL receptor knockout mice, which have high levels of LDL, there is decreased resistance to Candida (37, 38).

OxLDL also loses its normal anti-infective role against Candida. Worse, it inhibits production of antibodies against Candida albicans (63), thus actually hurting anti-fungal immunity.

Candida is an unusual pathogen that is unusually well-adapted to living in the human body. It has learned to turn an important part of human immune defense to its own advantage.

Conclusion

High serum cholesterol protects against a host of bacterial and viral infections and some parasites, but increases risk for Candida fungal infections.

Related Posts

Other posts in this series include:

References

[1] Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol. 2010 Apr;54(4):246-53. http://pmid.us/20377753.

Beef Tallow

By reader request, we’re working on Perfect Health Diet versions of classic American foods. Next week we’ll start with French fries, then maybe chocolate chip cookies.

I think I mentioned once that we’ve been cooking with beef fat a lot. This is a little healthier than plant oils, since it has more phospholipids, cholesterol, and usable nutrients, lacks plant toxins, and is low in polyunsaturated fat.

Since we’re using beef fat to good effect in a lot of recipes, it’s about time to show how we render it.

Rendering Beef Fat

We buy blocks of beef fat from our local Asian supermarket. Here’s one:

This 1.28 lb (0.6 kg) package costs less than $2 and will make about 2 cups (0.5 liter) of oil.

We normally keep the package in the freezer until a day before rendering, when we move it to the refrigerator to let the fat soften a little. The first step is to cut the fat block up into pieces with a knife, and transfer it to a suitably sized pot:

Many people add some water to the fat at this stage. The good side of this is that the water prevents the fat temperature from rising above 100ºC / 212ºF. The bad side is that it makes a mess. We prefer to do it without water.

Start heating the fat at a very low setting and use a potato masher to break up the fat into finer pieces and squeeze out oil:

Soon it will look like this:

As soon as there is a significant amount of liquid oil, pour the fat and oil through a strainer to separate the liquid and solid fats:

The brown ceramic bowl is where we’re collecting the liquid oil. The solid fat caught in the strainer gets returned to the pot for more heating.

The reason for pulling out the oil is that beef fat contains a variety of components which have different melting points. In general, triglycerides containing short-chain and polyunsaturated fats have lower melting points, triglycerides containing long saturated fats high melting temperatures. Fats with lower melting points tend to be more chemically fragile. You don’t want to overheat the fragile oils, damaging them; but you need to be able to apply more heat to render the high melting temperature fats. The solution is to separate the oil from the fat several times, and gradually turn up the cooking temperature each time.

After the solid fat has been returned to the pot, you can turn the heat up a little bit, but not too much. We’ll do maybe 4 straining cycles before we’re done.

Here’s the oil collecting in our bowl:

At the end, this is what remains:

We don’t consider these cracklings to be healthy, and discard them, but Wikipedia says that cracklings “are part of all traditional European cuisines.”

The oil can be returned to the refrigerator and used as needed as a cooking oil. It solidifies upon refrigeration, but can be cut into pieces with a knife.

The whole process takes about 30 minutes.

Conclusion

At $4/liter (quart), rendered beef fat is cheaper than olive oil or coconut oil. Since few people buy beef fat, and many butchers trim fat from meat and discard it, you may even be able to get some free from a friendly butcher.

Rendered beef fat stands up to high cooking temperatures, is more nutritious than plant oils, and tastes great. Especially, as we’ll see next week, on French fries.

Around the Web; Cancer, Infections, Cholesterol, and Nitrates Edition

[1] Summer Meet-up: We’ve chosen July 23 for the meet-up at Plum Island off Newburyport. We’ll be at the beach at the south end of the Island between 4:30 pm and 6:30 pm and will be happy to picnic and hang out with anyone who cares to join us.

[2] Interesting posts and news: A six year old cancer patient, Diamond Marshall, got a visit from the Kate, the Duchess of Cambridge. What struck me was that her mother had died of cancer at age 32, when Diamond was 18 months old. Coincidence? Or contagion?

Before you answer: a new paper reports that IL-8 and CRP – both markers of infection – predict future cancer.

Chris Kresser interviewed Emily Deans, a combination that is self-recommending. Among many noteworthy tidbits, Chris is working with an 83-year-old Alzheimer’s sufferer who is doing well on a Perfect Health Diet-style ketogenic diet.

Evidence that nitrate-rich foods, such as spinach and beetroot juice, are beneficial for vascular health and athleticism came out recently. Julianne Taylor has a few links. I might add that nitrates are also beneficial for immune function. Another recent study showed that exercise upregulates nitric oxide which is then stored as nitrites with long-term benefits. Nitrates also lower triglyceride levels and help cure hypertension. So, eat your spinach and exercise!

Seth Roberts reminds us of a good quote (modified from Beveridge): “Everyone believes an experiment except the experimenter; no one believes a theory except the theorist.” In another post, Seth reports that health in the US as measured by age of disease onset has not improved since the 1960s, life expectancy in the US peaked in 2007 and is now declining, medical care has stagnated, and this should be a big story.

Seth is right. Deteriorating results with exploding costs is not a good combination. We believe a focus on diet, nutrition, and antimicrobial medicine would deliver far more benefits at much lower cost than the current approach.

Pål Jåbekk notes something I’ve been meaning to blog about for quite a while:

[Y]et another study finds that overweight people have higher life expectancy than their lean counterparts, albeit with greater risk of disabilities. Perhaps our focus should be on natural foods and exercise, rather than on the significance of some extra padding. (study here)

Pål also gave us a thoughtful response to Stephan’s series on food reward. Highly recommended.

Hans Keer added starch to his diet, felt better, and decided he needs a new name for his site: Goodbye CutTheCarb.

Giardia infections account for 6.5% of cases of IBS in Italy. If you have digestive problems, it’s probably due to some kind of infection.

Via Craig Newmark, epidemiologist Tara C Smith:

As I’ve laid out this week (part 1part 2part 3), the realization that a fairly simple, toxin-carrying bacterium could cause a “complex” and mysterious disease like hemolytic uremic syndrome came only with 30 years’ of scientific investigation and many false starts and misleading results.

Infections should be the first suspect in any disease, not the last.

We mentioned the Flynn effect in our book: intelligence rose steadily through most of the 20th century. A group of economists offers a possible explanation: Lead poisoning caused depressed IQ in the 19th and early 20th century, and cessation of the use of lead in plumbing gradually returned IQs to normal.

Nothing to do with health, but very entertaining: Steve Sailer on Racehorse Haynes.

[2] Just to show how cultured we are, some classical music: Beethoven’s Fifth translated into sign language.

[3] The turtle doesn’t seem worried:

Via Yves Smith.

[4] It’s not so bad to be the smallest loser: If I do a blog post on why the overweight live longer, this might be a good place to start. In mice on calorie-restricted diets, those who lost weight quickly had shortened lifespans, those who lost little weight had lengthened lifespans:

[S]trains with the least reduction in fat were more likely to show life extension, and those with the greatest reduction were more likely to have shortened lifespan…. [F]actors associated with maintaining adiposity are important for survival and life extension under dietary restriction.

Having trouble losing weight? Maybe you’ll have a few extra years to figure it out.

[5] High serum cholesterol is healthy: In a paper reviewed by Dr Briffa, Japanese investigators provide further support to an idea that I believe we discussed in our book: serum cholesterol protects against stroke.

People with TC over 6.2 mmol/l (240 mg/dl) had a 77% lower risk of stroke (96% lower chance of hemorrhagic stroke) than those with TC below 4.1 mmol/l (159 mg/dl).

It looks like high serum cholesterol almost totally eliminates hemorrhage risk. Worried about stroke? Ask your doctor how you can raise your cholesterol.

[6] How do you do it? Dr. Walter Willett knows: In our book we quoted Dr. Walter Willett of the Department of Nutrition at the Harvard School of Public Health disparaging coconut oil. Dr. Willett has become friendlier toward fat in recent years, and when we saw he was re-addressing coconut oil in the Harvard Health Letter, we hoped to find an endorsement. Alas, he still favors vegetable oils. The trouble with coconut oil is that it raises serum cholesterol:

I don’t think coconut oil is as healthful as vegetable oils like olive oil and soybean oil, which are mainly unsaturated fat and therefore both lower LDL and increase HDL. (http://pmid.us/21702109)

[7] Shou-Ching’s photo art:

[8] Not the weekly video: Evidence that nurture defeats nature:

Via The Anchoress.

[9] Weekly video: Plains Milky Way from Randy Halverson: