Vitamin D Dysregulation in Chronic Infectious Diseases

Posted by on August 21, 2010 45 comments

Commenter qualia recently got his serum 25-hydroxy vitamin D levels tested and found a surprising result: He had doubled his vitamin D intake from 5,000 IU to 10,000 IU per day, but his 25(OH)D levels didn’t budge – they were at 61 and 62 nmol/l, equivalent to 24.4 ng/ml in American units.

24 ng/ml is well below the optimal level for healthy people of 40 ng/ml. When a healthy person supplements vitamin D, the serum 25(OH)D level usually rises linearly with dose up to about 40 ng/ml, then it rises very slowly thereafter as the body tries to keep 25(OH)D from rising by putting vitamin D into storage.

So it was natural for qualia to expect his serum 25(OH)D level to rise when he doubled his dose.

But it didn’t. The stability of his 25(OH)D levels suggests that his body has reached an equilibrium at 24 ng/ml. Instead of plateauing at 40 ng/ml with abundant vitamin D3 as a healthy person would, he is plateauing at a lower level.

Why does that happen?

Well, I don’t know. But I would like to provide qualia with a little bit of background, because this could be a clue that helps diagnose his condition and optimize treatments.

Normal vitamin D regulation strictly controls 1,25D levels

I suggested in the comment thread that qualia get his 1,25D levels measured as well as 25(OH)D.

Levels of 1,25D are not routinely measured, even in scientific studies, because they rarely vary. Blood levels of 1,25D control calcium homeostasis and are tightly regulated. In healthy people, as vitamin D intake rises from zero, serum 1,25D levels shoot up to normal levels before 25(OH)D levels reach 12 ng/ml. They then stay in a normal range no matter how high 25(OH)D levels rise. The kidney is the primary controller of blood 1,25D levels. The normal range is about 16 to 42 pg/ml (42 to 110 pmol/L).

While all human cells can convert 25(OH)D to 1,25D, most cannot release 1,25D into the blood. 25(OH)D freely crosses cell membranes and maintains the same level throughout the body; but 1,25D does not cross membranes. This allows every cell in the body to “personalize” its 1,25D levels to its own needs.

Both 25(OH)D and 1,25D are active ligands for the Vitamin D Receptor (VDR), a nuclear receptor.  [1] When either 25(OH)D or 1,25D binds to the VDR, the compound is imported into the nucleus, where it combines with a vitamin A-activated Retinoid X-Receptor (RXR) to form a transcription factor which, among other roles, upregulates production of antimicrobial peptides (AMPs) that are crucial for cellular defense against intracellular pathogens.

The difference between 25(OH)D and 1,25D is that 1,25D is about fifty-fold more likely to bind to the VDR than 25(OH)D. So by converting more 25(OH)D to 1,25D, cells can upregulate their VDR activation and upregulate their immune defense against pathogens. Meanwhile, uninfected cells can keep their 1,25D levels low. Across human cells, there is a thousand-fold variation in the rate of conversion of 25(OH)D to 1,25D. [1]

In chronic infectious diseases, blood 1,25D is dysregulated

However, in people with chronic infectious diseases, 1,25D levels range all over the map, and are largely uncorrelated with 25(OH)D levels.  Here is a scatter plot from a paper by Dr. Greg Blaney [2]:

The patients in this sample were 100 chronic disease patients: 29 with fibromyalgia, 27 with chronic fatigue syndrome, 12 with post-treatment Lyme Disease, 9 with metabolic disease, 6 with osteoarthritis, 4 with irritable bowel syndrome, 4 with psoriatic arthritis, 3 with multiple sclerosis, 3 with seronegative arthritis, and 27 with other diseases.

Probably all of these diseases are caused by chronic parasitic infections.

A few things to note from this plot: (1) 25OHD levels in a lot of chronic disease patients cluster around the 61 nmol/L level that qualia has; and (2) most chronic disease patients have 1,25D levels well above the normal range, even though their 25OHD levels are mostly below the optimal level in healthy people.

What Causes 1,25D Dysregulation?

Here’s where we get into speculation. There just hasn’t been research exploring this question. Researchers are only just realizing that these diseases are infectious in origin and that vitamin-D-mediated innate immunity is critical to the intracellular immune defense.

Rather than speculate, I’m just going to mention a couple of possibilities.

First, in granulomatous diseases like sarcoidosis, it’s common to have low 25(OH)D and very high 1,25D. Granulomas are nodules where immune cells have been unable to eliminate some foreign matter and instead have built a barrier around it that walls it off from the body.  Granulomas often release 1,25D to the body. Some other granulomatous diseases: 

  • Tuberculosis
  • Leprosy
  • Schistosomiasis
  • Histoplasmosis
  • Cryptococcosis
  • Crohn’s disease

These are all infectious diseases, some of them protozoal in origin.

Second, nearly all human pathogens manufacture proteins or RNA that interfere with the innate immune response. Some are known to interfere with the VDR or with other aspects of vitamin D biology. (The HIV virus blocks the VDR entirely, one reason why it predisposes AIDS patients to infections.) It’s possible that vitamin D dysregulation is brought about by direct pathogen actions to disrupt cellular vitamin D pathways.

Conclusion

The only thing we can conclude with confidence from qualia’s vitamin D tests is that he must have a chronic infectious disease … but he knew that already.

Qualia would be best served by getting advice from an infectious disease specialist with experience in chronic diseases. Such a doctor might be able to narrow down the diagnosis. A diagnosis would help determine which antibiotics might be appropriate to help fight the infection.

Until a doctor’s diagnosis or qualia’s personal experience indicates otherwise, it’s probably prudent to continue with a reasonable intake of vitamin D and to increase iodine as quickly as possible. (Even this is not certain: the standard advice is to minimize vitamin D in granulomatous diseases.) Other infection-fighting supplements, like vitamin C, N-acetylcysteine, and glutathione are likely to be helpful also.

Finally, I always recommend that anyone with a chronic disease find a good discussion forum, like the one at http://cpnhelp.org, and try to find people with similar disease histories and learn from their experiences.

Best of luck, qualia, and please keep us posted.

References

[1] Lou YR et al. 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. J Steroid Biochem Mol Biol. 2010 Feb 15;118(3):162-70. http://pmid.us/19944755.

[2] Blaney GP et al. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. 2009 Sep;1173:384-90. http://pmid.us/19758177.

Why You Shouldn’t Supplement Calcium

Posted by on August 20, 2010 47 comments

Much of the advice handed out by medical doctors is unreliable.  One reason is that the research on which that advice is based is often conducted by specialists who overlook effects beyond their scope of professional interest.

We’ve mentioned previously the example of statin research. Statin studies are generally performed by cardiologists and in the U.S., many statin studies reported only heart attacks and other cardiovascular events as endpoints, not total mortality, cancer, or infectious disease. This method of evaluating drugs would show a lethal neurotoxin to be the best cardiac treatment ever:  In the neurotoxin group not a single patient would die of a heart attack!

A similar myopia has occurred in osteoporosis research, where doctors have focused on the effect of calcium supplements on bone density or fracture rates but often do not evaluate the effect of the supplements on overall health.

But other effects have to be considered, given that:

  • Calcification of coronary arteries may be the best single indicator of heart attack risk. [1]
  • In the Nurse’s Health Study, supplementation of calcium increased the risk of calcium oxalate kidney stones by 20%. [2]
  • Calcium is a strong promoter of biofilm formation in most pathogenic bacterial species. [3] It also likely promotes formation of Candida albicans (fungal) biofilms. As a result, it can aggravate bowel disorders and infectious diseases.

Clearly, calcium in the wrong places – a problem that could be exacerbated by calcium supplementation – is a major health risk.

What causes calcium to go in the wrong places? Deficiencies of vitamin D and vitamin K2 are common reasons. Deficiencies of both are widespread. Vitamin K2 deficiency is a known cause of vascular calcification.

A few years ago, a group of New Zealand researchers conducted a randomized clinical trial that found that over five years, older women taking calcium supplements doubled their risk of heart attack compared to women taking a placebo. [4]

Now, the same group has conducted a systematic review of calcium supplementation studies which confirms the link between calcium supplementation and heart attacks. Dr. Mark Bolland of the University of Auckland, New Zealand, and colleagues report that calcium supplementation increases the risk of heart attack by 31%, the risk of stroke by 20% and the risk of death by 9%. [5]

In an accompanying editorial, Dr. John Cleland writes:

Calcium supplements, given alone, … are ineffective in reducing the risk of fractures and might even increase risk, they might increase the risk of cardiovascular events, and they do not reduce mortality. They seem to be unnecessary in adults with an adequate diet. Given the uncertain benefits of calcium supplements, any level of risk is unwarranted. [6]

We concur. A healthy diet, including dairy and green leafy vegetables, not to mention a daily multivitamin (ours contains 200 mg calcium), should provide a sufficiency of calcium as long as vitamin D levels are normal. If you’re worried about bone health, supplement with vitamins D, K2, and magnesium citrate – not calcium.

[1] Budoff MJ et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol 2007;49:1860-1870. http://pmid.us/17481445. 

[2] Curhan GC et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997 Apr 1;126(7):497-504. http://pmid.us/9092314.

[3] Kierek K, Watnick PI. The Vibrio cholerae O139 O-antigen polysaccharide is essential for Ca2+-dependent biofilm development in sea water. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14357-62. http://pmid.us/14614140.  Geesey GG et al. Influence of calcium and other cations on surface adhesion of bacteria and diatoms: a review. Biofouling 2000; 15:195–205.

[4] Bolland MJ et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. 2008 Feb 2;336(7638):262-6. http://pmid.us/18198394.

[5] Bolland MJ et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341:c3691. doi: 10.1136/bmj.c3691. http://pmid.us/20671013.

[6] Cleland JG et al. Calcium supplements in people with osteoporosis. BMJ. 2010 Jul 29;341:c3856. http://pmid.us/20671014.

What Makes a Supercentenarian?

Posted by on August 18, 2010 103 comments

Centenarians live to 100; “supercentenarians” live to 110. It is a much more selective club.

There are an estimated 600 supercentenarians in the world, whereas the number of centenarians probably exceeds 600,000. There are about 100,000 centenarians in the US, 40,000 in Japan, and 8,500 in England and Wales. [1] Meanwhile, only about a dozen people in the world may currently be age 115 or older. The oldest person who ever lived, Jeanne Calment, reached age 122. [2]

As I mentioned yesterday, I have a Google Alert for centenarian stories and have been reading about them for some time. One thing I’ve found is that most centenarians don’t seem to think very much about their diets (which protects them from the food pyramid!), but supercentenarians tend to be very picky about what they eat.  Supercentenarian diets come in two basic flavors:

1)      Calorie-restriction and intermittent fasting.

2)      High (saturated and monounsaturated) fat low-carb diets.

We present some supercentenarian stories in the diet book; here are a few. First, some fat lovers.

Jeanne Calment “ascribed her longevity and relatively youthful appearance for her age to olive oil, which she said she poured on all her food and rubbed onto her skin” [2]. She also drank wine and ate chocolate every day. Olive oil, wine, and chocolate — you can’t get much healthier than that, as long as you get some vitamins on the side, and don’t let too much sugar in.

Gertrude Baines of Los Angeles lived to 115 on extremely healthy diet – bacon, chicken, and ice cream:

Gertrude Baines, who lived to be the world’s oldest person on a steady diet of crispy bacon, fried chicken and ice cream, died Friday at a nursing home. She was 115. [3]

When Edna Parker of Indiana died at age 115, Governor Mitch Daniels was impressed by her diet:

Parker especially enjoyed eggs, sausage, bacon and fried chicken. “I guess we’ll have to rethink lard,” Daniels quipped after hearing about her high-fat diet. [4]

The other longevity strategy is calorie restriction. Among the pioneers was Luigi Cornaro, a medieval Venetian nobleman who lived to 98, maybe over 100. Wikipedia explains:

Finding himself near death at the age of forty, Cornaro modified his eating habits on the advice of his doctors and began to adhere on a calorie restriction diet. Twelve ounces of solid food and fourteen ounces of wine was the daily allowance he allowed for himself initially. He later reduced his daily food intake to no more solid meat than an egg.

His first treatise was written when he was eighty-three, and its English translation, often referred to today under the title The Sure and Certain Method of Attaining a Long and Healthful Life, went through numerous editions. [5]

Intermittent fasting (say, confining food to an 8-hour window each day) is a great way to implement calorie restriction.  A practitioner is Walter Breuning of Great Falls, Montana:

So what does the world’s oldest man eat? The answer is not much, at least not too much.

Walter Breuning, who turned 113 on Monday, eats just two meals a day and has done so for the past 35 years.

“I think you should push back from the table when you’re still hungry,” Breuning said.

At 5 foot 8, (“I shrunk a little,” he admitted) and 125 pounds, Breuning limits himself to a big breakfast and lunch every day and no supper….

“You get in the habit of not eating at night, and you realize how good you feel. If you could just tell people not to eat so darn much.”…

And for his birthday lunch he got his favorite: liver and onions. [6]

I like that: liver and onions. Nutritious and fatty. You don’t find supercentenarians eating cake on their birthdays!

Fasting, however, can be taken too far. Sogen Kato’s strategy was ill-conceived:

Tokyo’s oldest man is no longer the city’s reigning centenarian….

Officials grew suspicious earlier this year when they attempted to visit [Sogen] Kato, who was to turn 111 last month. His family refused to let anyone in to see him, and repeatedly chased welfare officials away.

Eventually returning with police, the welfare officials discovered a mummified corpse, believed to be Kato, lying on a bed in his underwear and pajamas.

He is believed to have died in 1980 at the age of 81.

Kato, born in 1899, had long been believed to be one of the world’s oldest people.

Police suspect Kato’s family — his 79-year-old daughter and two grandchildren — had hidden Kato’s death in order to keep collecting his pension. They reportedly received upwards of 9.5 million yen (about $190,000).

The family, however, has an alibi: they claim Kato had “confined himself in his room more than 30 years ago and became a living Buddha,” according to a report by Jiji Press. [7]

Thirty-year fasts rarely work. If you do decide to become a living Buddha, ask for some bacon, eggs, liver, wine, and chocolate with your Zen.

References

[1] Max Planck Institute for Demographic Research; http://www.csmonitor.com/World/2010/0810/Supercentenarians-around-the-world/Italy;  http://en.wikipedia.org/wiki/Centenarian.

[2] http://en.wikipedia.org/wiki/Jeanne_Calment.

[3] “World’s Oldest Person Dies in L.A. at 115,” MSNBC.com, Sept. 11, 2009.

[4] Elaine Woo, “Edna Parker dies at 115; former teacher was world’s oldest person,” Los Angeles Times, Nov. 28, 2008.

[5] http://en.wikipedia.org/wiki/Luigi_Cornaro.

[6] Sydne George, “Two-meal diet aids in oldest man’s longevity,” USA Today, Sept 24, 2009.

[7] Michael Sheridan, “Officials learn Tokyo’s oldest man, Sogen Kato, actually died 30 years ago; family kept body hidden,” New York Daily News, August 2, 2010.

What Makes a Centenarian?

Posted by on August 16, 2010 15 comments

What makes a centenarian?  One ingredient, I think, is home cooking.

I had some fun with a nutritional brain teaser not long ago. The point of it was that almost any food – including cookies, ice cream, and potato chips – can be healthy if the ingredients are good, and any food will be unhealthy if the ingredients are toxic. Unfortunately, most prepared foods in supermarkets, and many restaurant foods, are made with toxic ingredients. It’s a sad commentary on today’s world; but if you want a long life, it’s almost essential to cook your own food.

I get a daily Google alert with news stories about centenarians. One of the most common features is that centenarians like to cook. The following three stories all came on the same day:

Via the Leesburg (Florida) Daily Commercial:

Great-great grandmother Mary D. Nix, 101, has a zest for life and believes it’s vital to live by the Golden Rule.

“I’m going to keep on living,” she said….

Born on July 28, 1909, in Leary, Ga., she married her husband, Elijah, when she was 16. The couple lived in Tangerine and Nix worked for more than 40 years as a domestic housekeeper.

“She worked for rich people all of her life, keeping the houses cleaned, their dinners cooked, and children fed,” said Thelma Hayes Wooden, the second oldest of Nix’s 17 grandchildren.

“She still thinks a woman’s job is in the kitchen,” Wooden said with a chuckle, recalling her grandmother would share advice with her family and others in her care.

Via the Burton (Staffordshire, UK) Mail:

The birthday girl said she used to enjoy cooking, knitting, sewing and gardening when she was younger.

Mrs Wright said: “I enjoy life very much and especially living in the home….

 “I’ve had so many highlights in my life and I couldn’t tell you what the secret to a long and happy life is, as I’m not sure.”

Via the New Haven (Connecticut) Register:

Her other son, Anthony Monaco of Denver, Colo., said his mother was feisty, a great cook and a hard worker. “She and my dad did a very good job of putting food on the table and raising us,” he said. “She would walk two miles from work to home each night, stop at the store and gather all the ingredients for that night’s dinner, come home, make dinner and get out the ironing board.

“She worked hard all day and pretty much all night. She also was a devout Catholic.”
Monaco died July 12 at age 100….

In her spare time, she liked to play cards, crochet, knit, cook, garden, walk, go to the casinos, dance and listen to Italian music.

Another common feature of centenarians is that they are cheerful and highly sociable. Centenarians always seem to have many friends.

Sociability does not always imply marriage: a surprisingly large number of centenarian women have never married. But marriage is no bar to longevity, as Wook Kundor of Malaysia shows:

Centena­rian Wook Kundor is all alone again.

Her husband Mohd Noor Musa, who is seven decades her junior, was rearrested for a drug-related offence on Sunday….

“He reneged on his promise not to indulge in drugs. But I can’t live without him,” she said when met here yesterday….

“I don’t know what is wrong with him. Probably he is bored without a steady job,” she said.

Wook Kundor said police had told her that her husband had tested positive for heroin….

She married Mohd Noor, her 23rd husband, five years ago.

Perhaps what makes a centenarian is this: “You can go to extremes with impossible schemes / You can laugh when your dreams fall apart at the seams / And life gets more exciting with each passing day / And love is either in your heart or on its way / Don’t you know that it’s worth every treasure on earth / To be young at heart.”