Micronutrients: Home Run or Hyperbole?
Julio is a fifteen-year-old Latino male from West Texas who weighs 400 pounds. He is Med-Flighted to San Francisco for an emergency liver transplant because his pathology shows severe fatty liver and scarring, known as nonalcoholic steatohepatitis (NASH) with cirrhosis, a condition associated with severe alcohol abuse. Although he has never consumed alcohol, he has imbibed at least a half-gallon of Coca-Cola every day since he was old enough to open the refrigerator. Julio’s transplant is successful, and he is discharged two weeks later, after being told to lose weight, stop drinking soda, and improve his diet. One year later, Julio is seen back at UCSF for a checkup. His diet hasn’t changed, the soft drinks continue, his weight has not declined, and an ultrasound shows fatty deposits in his new liver.
No doubt Julio’s new liver will suffer the same fate. Nonalcoholic fatty liver disease (NAFLD) is now the most common disease in America, affecting 45 percent of all Latinos, 33 percent of all Caucasians, and 24 percent of all African Americans, fat and thin. Considering this disease was not even described until 1980, the increase in prevalence to encompass one third of the entire adult population is astounding. Most of the people with NAFLD have no symptoms and don’t even know they have it. The majority of them will suffer no ill effects. But 5 percent of them will go on to develop NASH, with inflammation and scarring of the liver. And of those, 25 percent will develop cirrhosis, which will lead either to death or to a liver transplant, just as with Julio. When you do the math, that’s one million Americans dying from a nutritional disease; never mind all those who die from other complications of metabolic syndrome. Considering that this disease is completely preventable, this is a travesty. But is this an overnutritional disease or an undernutritional disease? Both, as it turns out.
While there are certain genetic predispositions (accounting for the higher prevalence in Latinos), you still need the excess energy coursing through the liver to develop the disease. Cue the sugar glut. We aren’t certain why the disease affects some severely, while remaining benign in others. There are several theories. Remember our biological enemies, the reactive oxygen species (ROS; see chapter 9)? Those whose livers can’t quench (detoxify) their ROS will progress on to NASH. ROSs damage lipids and proteins within the cell, which can cause cell structural damage or cell death. Removal of ROSs before they can do damage is the job of a subcellular structure called the peroxisome, which is where ROSs go to die. The chemicals that do the dirty work of knocking them off are known as antioxidants.
The “Triage Hypothesis”
It’s been over a hundred years since we discovered the link between vitamin B1 and beriberi, a disease of cardiac and neurological degeneration. William Fletcher discovered that eating polished rice stripped of its fiber caused the disease, while eating unpolished rice prevented it. Since then, we’ve learned of many vitamin or mineral deficiencies that lead to specific individual diseases with funny names (e.g., scurvy, pellagra). Fortunately, virtually all these micronutrient deficiency diseases have been essentially wiped out in America—either through the abundance of micronutrients in our diet or through specific supplementation in foods (such as giving folic acid to pregnant women to prevent neural tube defects in newborns). The concept that the diseases of metabolic syndrome might be due to inadequate micronutrient availability has been spurred on by animal studies and small-scale human studies. Nonetheless, the search for the “magic supplement” to reverse metabolic syndrome continues with fervor.
Enter Bruce Ames at Children’s Hospital Oakland Research Institute, who has been working in the field of nutrition for fifty years. He has put forward the “triage hypothesis” to explain our current metabolic dilemma. The premise is simple: Cells want to survive. Virtually every biochemical reaction requires one micronutrient or other, whether it is a vitamin, mineral, or biochemical compound. When micronutrients are in short supply, they are triaged to these reactions to maintain cell viability. Their relative deficiency then deprives secondary reactions, which are less important to short-term survival but crucial for long-term cell integrity. DNA or protein damage that goes unrepaired can lead to either cancer formation or cell death. According to the triage hypothesis, acute micronutrient deficiency leads to one set of diseases (e.g., scurvy), while relative micronutrient insufficiency leads to another set of diseases (e.g., metabolic syndrome).
I Used to Care, but Now I Take a Pill for That…
As our collective health has declined over the past thirty years, the imperative to find the magic bullet that will forgive our previous indiscretions has only heightened. This has created the approximately $100 billion industry of “nutraceuticals.” Currently, more than 50 percent of America takes at least one form of nutritional supplement, hedging their bets. A trip to the local health food store or pharmacy will overwhelm even the most seasoned vitamin aficionado with options. Do any of these supplements exert any benefits? Maybe it doesn’t matter, since 71 percent of users say their belief is so strong that they will continue to consume the nutraceutical even if studies demonstrate a lack of efficacy.
Antioxidants: The Fountains of Youth?
Almost every advertisement for breakfast cereal shows the bowl dressed with a handful of blueberries. Perhaps this is to draw your attention away from the fact that the antioxidants in the cereal have been processed out and that the only way to rescue your meal is to supplement them back in the form of fresh berries. No doubt, more color means more antioxidants, and fruits and vegetables are packed with them. Antioxidants allow the plant to buffer the damage from its own ROSs when making its carbohydrates from photosynthesis. Can consuming them help us to battle our own?
There’s growing literature that “oxidative stress,” or the damage caused by ROSs, is the single most important factor contributing to the aging process. Different tissues generate ROSs by different means. Therefore, disparate antioxidants are required to help quench them to prevent various types of chronic diseases. Antioxidants come in many shapes and sizes, many of which have been considered as treatments for metabolic syndrome.1 The antioxidants vitamins C and E protect against lipid peroxidation (as in potato chips when they go rancid), though neither has been shown to improve vascular function or insulin resistance. In fact, high-dose vitamin E has been linked to increased rates of mortality.2 Although there are occasional “hits” among the treatment of metabolic diseases with antioxidants, most are near misses.
Vitamin D—The “Great Impostor”?
By far, the most enticing yet unrealized hope for the magic bullet that will cure all our ills is vitamin D. More has been written about this compound than all other vitamins, minerals, and supplements combined. Deficiency of vitamin D can occur either from lack of sunlight (which makes vitamin D in the skin) or lack of vitamin D in the diet. Vitamin D is certainly a godsend for children who suffer from rickets, a debilitating bone disease and seizure disorder due to a lack of vitamin D. We learned back in the 1920s that a teaspoon of castor oil (made from salmon liver) cured rickets, though we didn’t know why (much to the chagrin of the children forced to swallow it). In the 1950s it was discovered that a teaspoon of castor oil contained 400 units of vitamin D, so this became the dogma: we need 400 units of vitamin D per day (although recent studies suggest we need as much as 800 per day).
Could low vitamin D be at the heart of our chronic metabolic problems? Many scientists subscribe to this idea, and a subset of them have gone out on a limb to stake their claim to vitamin D as the cure-all for chronic metabolic disease. There is no doubt that vitamin D levels correlate inversely with all the core diseases associated with metabolic syndrome: diabetes, hypertension, and heart disease. But why is one third of America vitamin D deficient anyway? One reason is that we have been taught to avoid the sun like the plague. The second reason is that per capita consumption of milk, the primary source of dietary vitamin D, has declined by half over the past sixty years. Commensurate with the decline in milk consumption is the increase in sugar-sweetened beverages (soda and juice). You can’t untie the two with epidemiologic data, which is all we have so far. So which is the cause of metabolic syndrome? The dearth of vitamin D, the glut of sugar, or a combination of the two? Currently, not one study examines vitamin D levels and sugar consumption at the same time to determine which is the primary cause of metabolic syndrome and which is secondary.3
Resveratrol: The New “It” Compound
Perhaps the single biggest blockbuster in the field of nutraceuticals is in trials right now. Not since gingko biloba has a nutraceutical been so highly touted as has resveratrol, a compound found in small amounts in food but in high amounts in red wine. (Yes, you can have it all!) But this one has some staying power because of its mechanism of action in the right part of the cell. In animal models, resveratrol has shown beneficial effects on reducing inflammation produced by ROSs and, by doing so, preventing cancer, reducing atherosclerosis, reducing visceral fat, improving insulin sensitivity, and possibly even preserving neuronal function—all with virtually no side effects. The problem is that human studies are just getting started, and so far have been short term only. The most recent review4 suggests that while promising, resveratrol is not yet ready for prime time.
Contenders or Pretenders?
Many epidemiologic studies demonstrate correlations between low blood levels of antioxidants such as vitamin C and beta-carotene and the prevalence of metabolic syndrome. But are these micronutrient deficiencies the true cause of disease or just markers of an extremely bad diet? At this point, we just don’t know. We know that altering diet (eating more fruits and vegetables, limiting processed foods and sugar) to deliver more of these compounds is almost uniformly beneficial in improving the signs and symptoms of metabolic syndrome. But when these antioxidants are given as supplements, they usually fail miserably. This could very well be due to the beneficial effects of eating unprocessed foods, where you get both the fiber and the antioxidants as a bonus.
In clinical trials, vitamin E supplementation has flamed out not once but five separate times: (1) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, in which beta-carotene (the orange stuff in carrots and the precursor to vitamin A) and vitamin E given to heavy smokers increased their risk for cancer and ischemic heart disease; (2) in the Heart Outcomes Prevention Education (HOPE) Trial of 2005, in which vitamin E contributed to heart failure; (3) in the Women’s Health Initiative of 2005, in which ten years of vitamin E showed no benefit on heart disease or cancer; (4) in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) of 2009, in which the vitamin E group increased their risk for prostate cancer; and (5) in a 2008 Cochrane meta-analysis, in which vitamin E did not alter the rate of cognitive decline.
The Iowa Women’s Health Study has provided the most recent stake through the heart for the dietary supplement movement.5 This long-term and well-controlled study showed slightly increased risk of death with several dietary supplements (particularly iron). Of all of them, the only long-term benefit was found by taking calcium, which improved longevity through fewer broken bones. But you never hear about these failures, because no agency publicizes them and there is no pressure to remove the supplements from the market.
This is a real dilemma. Micronutrients matter—the biochemistry says so—except they don’t work when provided as supplements in clinical trials. How many studies do we need? Now you’re ready for the dénouement: Real food, containing endogenous micronutrients, prevents metabolic syndrome. Processed food causes metabolic syndrome. And nutritional supplements can’t reverse that which has previously been destroyed.6 So why does real food work while supplements don’t?
The Right Stuff: Real versus Manufactured
Face it, we got spoiled by previous successes. All the classic vitamins work to cure their respective nutritional deficiencies, even when they are supplied in a pill. Perhaps because the only thing that’s wrong is the undernutrition, the vitamin deficiency itself. But metabolic syndrome is far more complicated. Treating overnutrition is a much tougher nut to crack. Replacing something that’s missing is a whole lot easier than taking away something that’s in excess. Kind of like pudding. You can always put it back on the stove. But once overcooked, you might as well throw it away. There are five theories as to why:
1. Various items added during the processing of food, such as sugar and other preservatives, are even more toxic than we think (see chapter 12). Something that ubiquitous and potent may just dwarf the beneficial effects of any nutritional supplement.
2. The processing of food removes something even more valuable than the micronutrients, which remain un-replaced. Could there be something else in real food that is missing in processed food? Could it be the fiber itself? Could fiber be the real antidote to metabolic syndrome while everything else is just window dressing?
3. The simple act of food processing removes the food’s native micronutrients, just as the fiber is stripped. After all, many micronutrients travel with the fiber. Recall the beriberi story—it was the polished rice, stripped of its fiber, that lost its native vitamin B1. Flavonoids, folate, and many other micronutrients are decimated by food processing. While it’s enticing to think that we can put them back with a pill, the data support that once a food is “biologically” dead, it’s unlikely that you can revive it with a sprinkling of a nutraceutical.
4. Some antioxidants when furnished in high supply are instead oxidants, performing the opposite effect. The perfect example of this is iron. Iron is needed to make all the scavenger enzymes work, but too much iron brings its own level of oxidation—it’s called rust, which like the “browning reaction,” occurs inside you as well.
5. Nutraceutical supplements aren’t subject to the same rigorous quality control standards as pharmaceuticals. The Dietary Supplement Health and Education Act of 1994, passed by Congress, virtually assured the nutraceutical industry a free pass on demonstrating both safety and efficacy of their products. In 2008 the IOM crafted lower limits for these substances, but no tolerable upper intake limits—which means that companies don’t have to assure potency. Can you assure consistency from one batch to the next? Can you even assure that the native plant was accurately identified and put in the correct supplement? And does consuming 1,000 percent of your USDA recommended daily allowance of vitamin C have any demonstrable effects on fighting the common cold? The only way that the industry has gotten away with this so far is that the FDA doesn’t regulate them.
One thing’s for sure: the $123.9 billion (in 2008) nutraceutical industry, accounting for 6 percent of all food dollars, is a house of cards. Better to go with the tried-and-true answer to combat metabolic syndrome. We know it works, it has even more positive effects for our bodies, it’s a lot cheaper, and it tastes better. So what is this magic bullet? Unfortunately for Julio, it’s not a new liver. Rather, it’s called real food.