Endodoc

Yesterday I wrote about the clinical entity failure to thrive (FTT).  This morning I realized that I had not really addressed the question of endocrine gland disorders that can be associated with FTT.  Probably, the reason I did not mention endocrine disorders was that they do not often cause FTT and if they do, the signs and symptoms usually make it easy to make a diagnosis.

As I discussed in the previous entry, the key feature in all patients with FTT is poor weight gain, with or without short stature.  With only a few exceptions, endocrine disorders that cause short stature are rarely associated with poor weight gain.  For example, patients with either growth hormone deficiency, hypothyroidism or Cushing’s disease (glucocorticoid excess) typically present with short stature, but are generally overweight for height.  The endocrine conditions that typically present with poor weight gain (with or without short stature include type 1 diabetes mellitus, adrenal insufficiency (i.e., Addison’s disease), and conditions associated with hypercalcemia such as hyperparathyroidism.  Usually, the signs and symptoms for these disorders are such that very little detective work is needed to figure out what the problem is.  The one exception might be adrenal insufficiency; I have been amazed at how often that diagnosis is delayed for a long time if the patient is being followed by a primary care doctor, despite many clues from the medical history and physical examination.  I suspect the main difficulty in diagnosing adrenal insufficiency, is that the various disorders that cause adrenal insufficiency are rare and many physicians (not pediatric endocrinologists) have little or no experience in dealing with the problem.  Be warned.

A couple of weeks ago I received a telephone call from SS, one of my daughter’s close friends from college.  SS, who lives in New York City, called my daughter, who lives in California, because she was concerned about her younger sister’s (RS) daughter, KS .  RS had been worried about her daughter’s growth.  RS told her sister SS about the problem and SS promptly called my daughter; I suspect SS called my daughter because the daughter of a pediatrician would be expected to know almost as much as a pediatrician.  Right?  Anyway, my daughter called me and I was warned to be expecting a phone call from SS, which I got the next day.  SS wanted to know if I would be willing to talk with her sister.  Of course I agreed and talked with RS the next day.  I learned that KS was 16 months old and had  been  diagnosed with failure to thrive (FTT).  RS wanted to know what FTT was and what I thought should be done.  The situation was a bit complicated because RS lives in the Netherlands and was just visiting the U.S.  The family (RS, her husband, and 2 daughters, MS, age 4 years, and KS) has health insurance in the Netherlands but no coverage in the U.S.  The diagnosis of FTT had been made by a pediatrician in New York who recommended that a large number of laboratory studies be carried out as soon as possible.  One question RS had for me was whether the tests needed to be done immediately or could wait until the family returned to the Netherlands in about 2 weeks; the pediatrician estimated that the tests would cost about $5000-$10,000 (blood work, x-rays, and MRI, etc).

The Medical History

I first told RS that I would be happy to discuss things with her but that she needed to understand that it is always risky to get “curbside” consultations and that without actually seeing a patient, it is difficult for a physician to give a well-reasoned opinion,  and that my advice should be considered in that light.  KS was born full-term after an uneventful pregnancy.  There were no problems at birth and initially the infant seemed to do very well, following the 50% for height and weight until about age 6 months.  RS and her husband were of average height and their older daughter, MS was at about 60% for height and weight.  The infant was being exclusively breast-fed. After age 6 months, the infant slowed her growth rate, falling to about 40% for height and 5% for weight by age 1 year; at age 15 months, the height was still at about 40% but the weight percentile fell further, to about 2%.  At no time did the infant show actual weight loss.  KS seemed to be feeding well and was a happy baby although her development seemed to be a bit slower that that of her older sister; KS was babbling but still not walking.

The New York pediatrician who  saw KS  made the diagnosis of FTT based on the infant’s weight and the history of slow weight gain.  The pediatrician felt the physical examination was normal except for the weight and perhaps, slightly delayed motor development, and slightly decreased muscle tone.  As discussed above, the pediatrician recommended a series of studies but felt they could be delayed a few weeks (until the family returned to the Netherlands.  The pediatrician did order a complete blood count and basic blood chemistry tests (electrolytes, serum CO2, BUN, etc.) all of which showed normal results.  Hence, no anemia, and no evidence of kidney disease or metabolic disease associated with acidosis.

What is FTT, how is it diagnosed, and how is it treated?

The best definition I have yet seen of FTT was written by Cindy Christian and Nathan Blum in the textbook, Nelson Essentials of Pediatrics, 5th Edition (2006), Chapter 21, (Failure to thrive).  The authors wrote the following: “Failure to thrive (FTT) is a term given to malnourished infants and young children who fail to meet expected standards of growth.”  The authors went on to say that that the term FTT most often describes malnutrition related to environmental or psychosocial causes but that most children with FTT also have organic contributors.  The list of possible organic contributors is a long one and includes most every body system (e.g., genetic/congenital/anatomic, gastrointestinal, metabolic,  neurologic, renal, and hematologic disorders, as well as infections.  Thus, FTT is not really a specific diagnosis of anything but rather, a descriptor of certain signs and symptoms with poor weight gain always the “centerpiece.”  It’s sort of like a diagnosis of “limp,” which could be caused by anything from a rock in one’s shoe, to a serious bone or joint disease.  Regardless, once a paient is diagnosed with FTT,  every effort must be made to determine a specific etiologic diagnosis so that proper treatment, if any can be given in timely fashion.

How to sort through the myriad of diagnostic possibilities?

Once a diagnosis of FTT is made, the next step is for some knowledgeable health professional (e.g., nurse practitioner, pediatrician, pediatric endocrinologist) to get a detailed medical history.  The history should include as much information as possible about previous height and weight measurements and  laboratory test results.  In addition, the history should include detailed information about the infant’s feeding history and details about the family social history in an effort to uncover any potential environmental/psychosocial factors.  Next, a comprehensive physical examination should be performed that includes a developmental assessment. Well done medical histories and physical examinations are always “just what the doctor ordered” in any patient encounter, and in patients with FTT,  they are critically important.

The next step: developing a differential diagnosis

Armed with information from the medical history and physical examination, one can begin to develop a plan of action.  I usually start by asking myself 3 questions.  The first is whether, based on all the information available, I am reasonably confident the patient is normal and that the “poor” weight gain is/was a variant of normal and that no studies or treatment is needed.  Being reasonably confident is not the same thing as being 100% confident, and generally, such a patient should be seen for a follow-up clinic visit in the next 1-2 months.  The second question is whether I am reasonably confident the patient has a specific medical disorder that can explain the poor weight gain.  For example, if the history and physical examination strongly suggest a gastrointestinal basis for the poor weight gain, such as celiac disease, the next steps in the evaluation process are straightforward.  The third question is the most difficult one to deal with and is whether I am unable to decide whether the patient likely  is either normal or has some (as yet unknown) environmental/psychosocial and/or organic process to explain the poor weight gain.  Unfortunately, in my experience, even after a detailed medical history and physical examination, the answer to this question is often “yes,” necessitating considerable detective work.

Is the FTT merely a variant of normal growth?

It should be obvious that to determine if the FTT is not really FTT but only a normal growth variant, requires an understanding of normal growth.  I have discussed this subject in some detail in earlier entries but I will review things a bit for those of you who do not wish to hunt down the appropriate entries (I can’t even remember which ones, but they can be found by checking out entries in the growth disorders category.   Principle #1: children generally follow both weight and height growth channels very closely; if a child is at 50% for height at age 2 years, he or she is very likely to still be at that percentile at age 8 or 9 years of age.  Many normal children do not have height and height at the same percentile; it can be perfectly normal to be at 50% for height and 10% for weight and vice versa (but less desirable for a number of reasons that we will not discuss here).    There are 2 important exceptions to this principle; first, during infancy, children often do not stay in their height and weight channels.  Infants who are genetically programmed to be bigger than their height percentile at birth would suggest (to be precise, in children we pediatricians and pediatric endocrinologists, generally carry out length rather than height measurements up until age 2-3 years of age), show acceleration in both height and weight from the beginning, reaching the growth channel they will follow by about 1 year of age; premies often take somewhat longer.  For infants who are programmed to follow lower height and or weight channels than their height and or weight at birth, first follow the birth channels for about 6 months and then, gradually slow their growth rates- we call it “lag-down,” until about 18-20 months of age, at which point they track “like glue.”  The second exception to principle 1 is puberty.  All bets are off as to the growth rate (both height and weight) at puberty.  Children who are “destined” to end up at lower or higher height and or weight percentiles as adults than they followed during childhood, will generally fulfill their destinies.  Remember the following: Scottie dogs generally have Scottie dogs and Great Danes generally have Great Danes.  That saying is actually principle #2.

Back to KS

Remember KS, the 16 month old we were discussing?  Her growth pattern could be merely normal lag-down but I doubt it, since lag-down usually affects both height and weight.  Earlier, I didn’t mention that at the time of the visit to the pediatrician, RS was concerned that perhaps, KS was not getting adequate calories from the breast feeding alone.  KS decided to taper off the breast feeds and add table foods.  I got a follow-up from KS just the other day.  The family returned to the Netherlands, went to the clinic where the diagnosis of FTT was confirmed by a nurse practitioner, and an appointment was set up with a pediatrician; in the Netherlands, the primary care providers are often nurse practitioners.  But, RS told me that since decreasing the breast feeding and adding table foods ad lib, KS had been gaining weight like crazy and had progressed substantially with her development. So, in this instance it looks like the problem was inadequate calories and maybe a bit of vitamin D deficiency?  I am just speculating about the vitamin D deficiency but given that KS had not received any vitamin D supplementation and had been exclusively breast-fed, that’s a good possibility- vitamin D deficiency could explain the poor muscle tone and slow development.  The primary health care provider felt the problem was likely a nutritional one because of the much lower weight than height percentile and was betting on celiac disease or something like that (a reasonable hypothesis).  Anyway, we will need to wait until RS gives me another follow-up to find out if the problem in this case was more or less an environmental/psychosocial one rather than a systemic disorder.  I promise to let you know.  Finally, please do not infer from my entry that I am not a fan of breast feeding.  I think breast feeding is the way to go but that occasionally, problems do arise.  That’s why infants and children need regular check-ups by health care professionals who know all about monitoring growth (and breast feeding).  I suspect that for KS, part of the problem was related to the discontinuity in medical care because of the family travels between the U.S. and the Netherlands.  I am hoping things will turn out well.

A headline in the New York Times on Wednesday, June 22, 2011 caught my eye:  “Study finds higher risk of diabetes from statins.”  The report, written by Tara Parker-Pope,  summarized the results of a study published the day before in the The Journal of the American Medical Association (JAMA).  The investigators (Dr. Kausik Ray and colleagues) carried out some old-fashioned data-mining, analyzing results of 5 previously published studies,  and found that statins (e.g., Lipitor), a class of drugs used to treat high cholesterol levels, were associated with a slightly increased risk (12%) of developing diabetes mellitus.  For patients who took high doses of statins, the risk was about 20%.

Is this new and exciting information?

The association between statin use and slightly increased risk of diabetes is not a new observation; last year The Lancet published a study of 90,000 patients taking statins and showed an increased risk of about 9% (the present study included about 32,000 patients).  So, these new data are mostly “same old same old.”  In fact, I am not sure why the study got so much attention by the New York Times, other than many people take statins and article was published in JAMA.  Anyway, the article quoted Dr. Steven Nissen, a cardiologist from the Cleveland Clinic, who said he didn’t think the information was very important. What I found amazing was that neither the author of the newspaper article or any of the people quoted in the article raised the possibility that the study findings really had nothing at all to do with statins causing diabetes.  For example, maybe the association is related to the fact that more people who develop diabetes have lipid abnormalities and are more likely to be treated with statins?  Instead, the article focused on the possible mechanisms by which statins could lead to the development of diabetes.   The only way to answer this question would be to do a long-term randomized clinical trial in which patients with abnormal lipid levels were either treated with statins or just monitored.  I am not suggesting that such a study be carried out since it probably wouldn’t be ethical given the proven  benefits of statins to treat lipid abnormalities and decrease risk for the development of cardiovascular disease.  What I am suggesting is that those who write articles in newspapers and magazines about medical studies, be more careful to make sure readers understand the difference between cause/effect and association.  This was not even considered in this New York Times article.

Just last week, I wrote about the poor outcomes from studies on a new minimally-invasive approach to gastric stapling, via the oral route.  Now, I want to call your attention to an article published last week in the Archives of Surgery that raises questions about the safety and long-term success of current gastric banding procedures.  The study, conducted in Belgium was headed by Dr. Jacques Himpens,  looked at outcomes in patients who had laparoscopic gastric banding procedures performed between 1994-1997.  The study results were alarming; in about 30% of patients, the bands eroded and 60% required additional surgery.  Also, most patients were still quite overweight; patients had ended up losing well less than half of their excess weight.  The investigators concluded that gastric banding procedures “result in relatively poor long-term outcomes.”  The study was limited in that data were available on only about 60% of the total number of patients but it represents one of the few studies out there with long-term data on gastric banding procedures.  Of course, one could take a positive approach to the data- most patients were quite a bit less heavy than they were before the procedure, and about 60% of the patients expressed satisfaction with the surgery.  Anyway, these data illustrate a principle in medicine that I have often written about- one must weight risks vs. benefits for any treatment, be it growth hormone injections or gastric banding.  It is the unknown risks that pose the greatest dilemma in trying to decide if a proposed therapy is a good idea.

You probably know that a major earthquake and tidal wave hit Japan a few weeks ago.  One of the many problems associated with this catastrophe was damage to several nuclear reactors with leakage of radioactive materials, including radioiodine (I-131).   You may or may not know that exposure to radioiodine is associated with increased risk of developing thyroid cancer.  The risk is directly related to the exposure (i.e., radiation dose) and is highest in young children and pregnant women.   Much of what we know about the association between radio iodine and cancer risk comes from the experience at the  Chernobyl power plant  in Russia in 1984.  We know that exposure from breathing contaminated air confers greatest risk,  followed by ingestion of contaminated milk and fresh vegetables.  Children under age 10 years are at greatest risk.  Risks are also related to the distance from the radiation source- the damaged nuclear plants in Japan are more that 5000 miles from the west coast of the U.S.- that’s a long distance.  Risk is also related to time.  For radioiodine, the half-life is about a week, so that the exposure risks decrease rapidly over time.

What should people in the U.S. do to prevent/minimize risks for the development of thyroid cancer ?

Last week, the Pediatric Endocrine Society (formerly named in honor of Lawson Wilkins) published a letter summarizing the risk of exposure to radioiodine from Japan.  The letter was written by Andrew Bauer, a pediatric endocrinologist at Walter Reed Army Medical Center in Washington, D.C.    Dr. Bauer reviewed the situation and offered advice regarding the use of potassium iodine (KI) to high risk populations in the U.S. (i.e., young children and pregnant women).  Oral KI is highly effective in preventing radioiodine from being taken up by the thyroid, thereby effectively eliminating the risk of developing thyroid cancer from the exposure.  Dr. Bauer made clear in his letter, that at present, there is no reason to consider KI prophylaxis anywhere in the U.S.  I think it would be worthwhile for both pediatric endocrinologists and primary care doctors to read Dr. Bauer’s letter, but I haven’t yet figured out how to provide a link to the letter, unless you are a member of the Pediatric Endocrine Society, but I will try to do so.  Meanwhile, a number of other professional societies have published statements on-line (e.g., Radiation Risks to Health: a joint statement from the American Association of Clinical Endocrinologists, the American Thyroid Association, The Endocrine Society, and the Society of Nuclear Medicine, March 18, 2011).  So far all the experts are saying we should stay cool and avoid the temptation to stock up on KI.

Three entries in three days!  I must slow things down so that readers don’t expect a steady stream of entries.  Anyway, I want to update my entry from yesterday and add a few new items.

First, the on-line article in the New York Times March 16, 2011 regarding the demise of Satiety Inc., the company that had promoted gastric stapling via the oral route, was published in the paper version of the newspaper yesterday (“Hoping to Avoid the Knife,” written by Andrew Pollack).  The article is very well-written and is a good review of the entire field of bariatric surgery ( i.e., weight-loss surgery) and approaches that minimize the surgical aspects.

Second, there is another interesting article in the New York Times today about treating obesity.  The article is entitled “Warmed-Over Atkins? Don’t Tell the French,” written by Elaine Sciolino.  Why this article is in the Thursday Styles section of the paper and not the Business Section (where the Pollack article appeared) I haven’t a clue other than the subject is the very stylish French.  Anyway, the article discusses Pierre Dukan, the so-called “French Dr. Atkins.”  Dr. Dukan is not well known in the U.S., but in France he is a giant celebrity and there is even a term to describe his devotees, “Dukanistes.”  What prompted the article is the news that Dr. Dukan’s diet plan will be published in a North American edition (presumably for the first time, and presumably in English) entitled “The Dukan Diet.”  The article discusses the diet, which seems to me to be just about identical to the original Atkins Diet- high protein/high fat/low carbohydrate.  I have no comments regarding the Dukan Diet except that as I have said in the past, almost every diet ever dreamed up, works just fine, but I am not aware of any diets that have shown consistent benefit over the long haul.  Of course I know you will probably buy the book and try the diet.  Whatever.

Finally, I have a bit more about hCG.  I learned yesterday from a physician colleague of mine that hCG is available not only in drop form but also as an oral spray (e.g, KetoMist or ‘My Fat Cure’ Homeotherapeutic HCG Oral Spray).  This physician has been taking a spray dose of the stuff every day for about a year (his wife bought it for him).  He told me it is great stuff and that he lost 30 pounds over the past year.  I told him I was impressed and asked if he did anything else besides taking the spray to achieve such good results.  He smiled and told me that he cut way back on his calories and increased his exercise.  I bit my tongue and didn’t say a word other than to tell him he looked great.

I almost forgot my apology.  Yesterday I was trying to “clean up” my website and delete spam but keep the interesting reader comments.  Well, I managed to delete all of the comments.  Sorry.

Yesterday I wrote an entry on the use of hCG for weight reduction.  Here I want to add a few things about the post and tell you about 2 interesting articles on obesity.  First, regarding my comments about the hCG craze, I want to make clear that I was not trying to be critical about “alternative” medicine, just quackery.  I will be the first to admit that the scientific method has its limitations; many studies of this and that have either “proven” a benefit or lack of benefit for a particular treatment or procedure, where later studies have truly proven the opposite.  So, all of us (health care professionals and consumers) must maintain both a healthy optimism and skepticism about medical procedures and therapies that seem on the fringe.  Don’t get me wrong, I think use of hCG (either homeopathic drops or injections of the real stuff), is a really bad idea as a method to treat obesity.

Changing the subject a bit, I want to call your attention to two interesting articles.  The first, published today in the New York Times on-line (I suspect it will make it into the hard-copy paper in the next day or so).  The article was entitled “Hoping to Avoid the Knife,” and written by Andrew Pollack.  The article reported that the “scar-less” weight loss surgery technique developed by Satiety, Inc., turned out to be a bust and venture capitalists who put $86 million dollars into the project have pulled out of the project.  The idea was to avoid all the problems with general anesthesia and scars that come with traditional stomach shrinkage procedures used for weight reduction (e.g., gastric-bypass, lap-banding) and cut costs.  Anyway, apparently, the study results were not so hot.  What I found interesting about the article, other than the bad news for Satiety, Inc., was the long discussion about the current state of things with all types of surgical procedures for weight reduction.

The second article was published today the New England Journal of Medicine and is entitled “Obesity Prevalence in the United States- Up, Down, or Sideways.”  The article was written by Susan and Jack Yanovski and although it is an editorial, is a beautiful summary of the various recent data sets that have examined the prevalence of obesity in the U.S.  There are some differences in the data among the various data sets; one can debate whether the prevalence of obesity has stabilized or is still increasing but two things are clear.  First, the prevalence of obesity in the U.S. is astonishingly high and this poses a serious health threat.  Second, even if the overall prevalence is not increasing, the percentage of people with extreme obesity (BMI equal or greater than 40) is climbing steadily.  The authors offer a very interesting discussion about what we should do about the problem.  I highly recommend that you read the article.

As an endocrinologist, I probably should know quite a bit about all the various hormones out there.  But, somehow I fell down on the job.  It is only in the past week or so that I learned about the hCG/weight loss craze.  It’s all over the news and the internet.  The other night I saw 3 hCG ads on TV.  What is this all about?

Human Chorionic Gonadotropin or hCG for short, is a glycoprotein hormone that is produced mainly in the placenta (the fetus and various tumors can also make the hormone).  As the name implies, the hormone stimulates the gonads, akin to the pituitary gonadotropins, luteinizing hormone (LH) and follicule-stimulating hormone (FSH).  It was discovered in 1919 and within a few years it was found to be  useful as a pregnancy test.  The “A-Z test” (named for Asheim and Zondek) was based on the fact that the urine of pregnant women promoted ovarian follicular development, ovulation, and formation of the corpus luteum (the “scar” in the ovary formed after ovulation and the site of progesterone production).  In the 1930s it was established that hCG was a placental hormone.  In the 1940, the hormone was purified.  We now know that the hormone consists of 2 subunits, alpha and beta.  The alpha subunit is virtually identical to several other pituitary hormone alpha subunits including LH and FSH and thyroid-stimulating hormone (TSH).  In addition, the beta subunit of hCG is very similar to that of LH and, as we will discuss, hCG works a lot like LH.

What does hCG do?

Although the function of hCG in pregnancy is not completely understood, most experts believe the hormone is critical to maintain the function of the corpus luteum ( i.e., adequate progesterone production) during early pregnancy.  The hormone level in the blood (and urine) rises rapidly in early pregnancy, reaches a peak at about 10-12 weeks and then gradually declines to a steady but low level throughout the rest of  pregnancy.  Not surprisingly, the hormone level is higher in pregnancies with multiple fetuses.  Levels are very high in cases of maternal isoimmunization (i.e., Rh factor disease) and in women with hydatidiform mole or choriocarcinoma.

Clinically, other than its use as a pregnancy test, hCG has been used mostly as a fertility drug, in women to stimulate ovulation, and in men, to stimulate sperm production.  The hormone is also used by pediatric endocrinologists and urologists in an effort to coax undescended testes into the scrotum.  I do not think it is used much these days for this purpose

The use of hCG for weight reduction

The idea of using hCG as a diet drug seems to have come from the work of a British endocrinologist named Albert Simeons.  Don’t ask me why, but Simeons studied the use of hCG injections for weight reduction in pregnant women and overweight boys in India.   He found that treating these patients with extremely low-calorie diets (500 kcal/d) for several months at a time and low-dose hCG injections resulted in impressive weight loss that was mostly fat tissue, not lean body mass (i,e, muscle).  Apparently, the idea caught on and for quite a number of years, hCG has been widely used (but below my radar) as a weight-loss drug.  As best I can tell, there are no convincing scientific data to show any weight loss benefit from hCG (a very good reference on the subject is Lijesen GK et al: Br J Clin Pharmacol 1995;40:237-43).  Various medical professional organizations have issued warnings about the ineffectiveness of hCG for weight loss.

Homeopathic hCG

Perhaps, the most interesting development has been the rapid rise in the popularity of oral hCG, so-called “homeopathic hCG.”  This product comes in the form of drops and can be purchased from numerous sites on the internet.  The sites typically consist of pages and pages of testimonials and how to purchase the product.  I do not know if it is true, but an article in Wikipedia states that the U.S. Food and Drug Administration has deemed homeopathic hCG  an illegal substance and it is not protected as a homeopathic drug.  I am not aware of any credible scientific studies showing any health benefit from these oral products.   One would not expect any benefit since “real” hCG is only biologically active when taken by injection.  As you might expect, homeopathic hCG drops are very expensive, with typical treatment courses costing many hundreds of dollars.

Injectable  hCG

What about hCG injections?  There is no question that injected hCG is biologically active and has legitimate medical uses in the treatment of infertility.  In men, hCG acts about like LH to stimulate testis testosterone production.  In fact, hCG has been used by drug doping athletes to normalize testis size after they have taken high dose testosterone injections to enhance athletic performance; the testosterone injections inhibit LH secretion, resulting in shrinkage of the testes.  In women, the effects of hCG are complex.  The hormone can promote ovulation,  and as discussed earlier, it can help support the corpus luteum and progesterone production.  The hormone can also lead to increases in estrogen production by first stimulating synthesis of testosterone in the ovary which is then converted into estrogen by enzymes in the ovarian granulosa cells.  Unfortunately, in some patients, hCG injections can result in the ovarian hyperstimulation syndrome in which very large increases in testosterone occur.  The condition can be life-threatening with the development of massive edema and vascular thromboses.   Many other hCG side effects have been reported.  Of course, when used as fertility drug, hCG injections can greatly increase a woman’s chances of having a multiple pregnancy.    Anyway, if hCG doesn’t really help promote weight loss, it is my opinion that the possible therapeutic risks (many) outweigh any possible benefits (none proven).

What is most amazing to me is that apparently many insurers will cover the cost of hCG injections for weight loss if prescribed by a physician .  The hormone is marketed by several pharmaceutical companies (e.g., brand names include Chorex, Novarel, Pregnyl, and Profasi).  Even without insurance coverage, the cost of injectable hCG is quite low, about $2.00/injection (a good summary of the costs and side effects can be found at eHow.com).

Who said our health care system is broken?

I this afternoon’s mail, I got this week’s New England Journal of Medicine. To my surprise and pleasure, there was a review article about vitamin D written by Clifford Rosen (Rosen CJ:  Vitamin D insufficiency. New Engl J Med 2011;364:248-54).  The article does a far better job than I did in my last entry to discuss the vitamin D/calcium controversies.  I strongly suggest you check it out.

Recently quite a bit has been written about the apparent epidemic of vitamin D deficiency in the U.S.  There have been many newspaper articles written about the need to increase vitamin D and calcium intake to prevent weak bones and fractures.  As best I can tell, it is now the standard of care to measure vitamin D levels (as serum 25-hydroxy vitamin D or 25-OH vitamin D)) in all middle-age women and in elderly men and women.  It seems that DEXA scans (a way to quantify bone mineralization) have become almost as common as blood glucose measurements.  I have spoken to quite a number of people, mostly women,  whose doctors (primary care docs and OB/GYN docs) have measured their vitamin D levels, found them to be “dangerously low,” and have prescribed supplemental calcium and vitamin D.  So, do we really have an epidemic of vitamin D deficiency?  I would submit that it’s mostly nonsense.  I will try to explain.

First, there is no question that, weak bones (osteoporosis) are a problem in the elderly, particularly women.  The prevalence of pathological fractures (those resulting from only minor trauma), particularly of the hips and spine are significantly increased in seniors and are very serious indeed.  For the most part, osteoporosis in the elderly is the result of a number of factors including poor nutrition resulting in insufficient intake of vitamin D and calcium, decreased physical activity, and low levels of the sex hormones estrogen and testosterone.

Many people now take vitamin D and calcium supplements in an effort to keep their bones strong.  Widespread use of these supplements led to a recent consensus statement by medical experts regarding recommendations for calcium and vitamin D supplementation- really an effort to clarify just what calcium and vitamin D requirements are at different ages (see “Extra vitamin D and calcium aren’t necessary, report says,”  written by Gina Kolata, NYT November 30, 2010, page 1, A20).  We will come back to the report later in my entry.

Vitamin D and Calcium absorption

Calcium absorption from the gut is different than for minerals such as sodium and potassium which are almost entirely absorbed; the absorption of calcium is incomplete and dependent on the body’s “need” for calcium.  It is a good thing that calcium absorption is regulated since, unlike sodium and potassium, the kidneys cannot excrete excess calcium very well;  large calcium loads can cause serious damage to the kidneys.  Thus, the body normally absorbs just the right amount of calcium regardless of the dietary intake.  The rate of calcium absorption is controlled by vitamin D, primarily 1,25-diOH vitamin D, the active component (25-OH vitamin D and related compounds can also modulate calcium absorption somewhat).  The way this all works is that when the blood calcium drops even a slight amount, the parathyroid glands  secrete parathyroid hormone which, in turn, stimulates formation of 1,25-diOH vitamin D, which in turn, stimulates intestinal calcium absorption.  The process is modulated by other hormones such as growth hormone and estrogens, which have direct effects on the secretion of 1,25-diOH vitamin D.  Glucocorticoids (e.g., hydrocortisone) in high doses can inhibit calcium absorption but this effect can be overcome by increasing intake of vitamin D.

Calcium absorption can be decreased in conditions that decrease fat absorption which decreases vitamin D absorption.  Also, diarrheal states or any other conditions that increase intestinal motility, decrease calcium absorption.  Some intestinal conditions such as celiac disease directly inhibit absorption of calcium.  High fiber foods, particularly certain cereals can inhibit calcium absorption;  high fiber foods contain large amounts of phosphates (specifically, an organic phosphate, phytic acid, which contains inositol hexaphosphate) which blocks calcium absorption.   It is interesting that whole wheat flour contains large amounts of phytic acid but fortunately, the leavening process (adding yeast to bread), breaks down the phytic acid.

Absorption of calcium in dietary supplements  (e.g., vitamins) can be affected by the chemical form of the calcium.  Calcium supplements are generally either calcium carbonate or calcium citrate.  Calcium carbonate, the most common form of supplemental calcium, requires an acid environment for optimal calcium absorption.  Thus, diseases or drugs that decrease stomach acid inhibit calcium absorption.  The citrate form of calcium is soluble and does not require an acid environment for absorption.  So, if one is taking supplemental calcium that is in the carbonate form, it is usually recommended that the medication be taken along with or immediately after eating, which stimulates stomach acid production.  I have not seen any good data showing just how different absorption of supplemental calcium is when taken with food or on an empty stomach.  I doubt it matters much but just to be on the safe side, I suppose people should take calcium carbonate-containing supplements with meals.

Vitamin D is essential for normal growth and development.  Both deficiency and excess of the nutrient can have serious consequences.  Deficiency of vitamin D causes rickets, while excess can cause hypercalcemia and injury to many tissues, particularly the kidneys.  Vitamin D is formed from 7-dehydrolcholesterol, a cholesterol  precursor found in the skin.  Ultraviolet light converts the precursor to vitamin D.  Vitamin D2 (called ergo-calciferol) is formed from irradiation of the plant sterol ergosterol while vitamin D3 (called cholecalciferol) is formed from irradiation of 7-dehydrocholesterol.  Both vitamin D2 and D3 are as potent as vitamin D in treatment of rickets.

Vitamin D (and vitamin D2 and D3) is not metabolically active.  Rather, it is activated by first being converted to 25-OH vitamin D and then to 1,25-dihydroxy vitamin D.  The first conversion takes place in the liver and the second in the kidneys.  Both 25-OH vitamin D and 1,25-diOH vitamin D are metabolically active but the latter much more so (about 1000X more active).   Vitamin D is a fat soluble vitamin which can be stored in the body fat for many months and be slowly converted into the active metabolites.  This is a big problem in cases of vitamin D over dosage.  As a fat soluble vitamin (just like vitamins A, E, and K), vitamin D anbsorption is affected by conditions that inhibit fat absorption, such as certain intestinal diseases and deficiencies in the intestinal enzymes responsible for fat absorption.  Thus, it is important to consider the possibility of vitamin D deficiency in all patients who have fat malabsorption.  Likewise, people who ingest very low fat diets, may have somewhat decreased dietary or supplemental vitamin D absorption.  Of course, adequate exposure to sunlight, results in synthesis of all the vitamin D normally required.  Some drugs do affect conversion of vitamin D to 25-OH vitamin D (e.g., cimetidine, some anticonvulsants) and as one would expect, liver disease can affect synthesis of 25-OH vitamin D as well.  Kidney disease can affect synthesis of 1,25-diOH vitamin D.

For people taking vitamin D supplements, it is generally recommended that they be taken with food.  One recent study showed that vitamin D absorption was significantly increased when taken with the biggest meal of the day (Mulligan GB, Licata A: Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. J Bone Min Res 2010;4:928-30).  I am not sure how to interpret the results of the study.  There were only 17 study subjects and all had normal 25-hydroxyvitamin D levels at baseline.  I don’t doubt the fact that taking vitamin D supplements with meals, particularly high fat meals, increases vitamin D absorption.  What I question is whether it matters much for most people?  If levels of 25-OH vitamin D levels are normal, is higher better?  I have not seen any data to show any health benefits.  In fact, recent studies show no relationship between serum  25-hydroxy vitamin D levels and mortality rate.  Anyway, I suppose that for both calcium and vitamin D supplements, it makes sense to take them with food.

The Expert Committee Report

So, back to the recent expert report on vitamin D and calcium supplements.  The bottom line is that most people do not need vitamin D and calcium supplements and they may, in fact be harmful.  There are data to suggest that extra calcium can increase the risk of heart disease and compelling data to show that extra calcium increases risks for kidney stones and permanent kidney damage.  The Institute of Medicine convened an expert committee to examine the available data to determine just how much vitamin D and calcium people really need.  Much of the “push” to treat with calcium and vitamin D supplements was based on the misguided notion that levels of serum 25-OH vitamin D below 30 ng/ml were low.  Based on this standard 80+% of people in the U.S. were vitamin D deficient.  In fact, the committee concluded that levels between 20-30 ng/ml were just fine (in the “old days” the lower limit of normal for serum 25-OH vitamin D  was about 15 ng/ml and I suspect that has not changed at all).  Note: breast-fed babies DO need supplemental vitamin D.

What did change was the availability of new drugs called bisphosphonates to treat osteoporosis.  The pharmaceutical companies, perhaps aided by the endocrinologists,  pushed and pushed for more aggressive treatment of patients with weak bones.  A new disease entity was created- osteopenia.  This was defined as a condition in which the DEXA scan results showed  normal but below average bone mineralization.  To be sure, people with osteopenia are more likely to develop osteoporosis than those with higher bone mineral densities, but there was no scientific justification for treating large numbers of patients with bisphosphonates (and supplemental calcium and vitamin D) to improve their bone health.  We certainly had the opportunity to learn about the complications that can develop with use of bisphsphonates (e.g., jaw necrosis).

The expert committee updated the recommended dietary allowance (RDA) for calcium and vitamin D emphasizing that most people in the U.S. already receive enough of both nutrients to manage just fine without supplements.  For example, in women ages 51-70 years, the committee recommended calcium RDA of 1200 mg/d with a maximum of 2000 mg/d; the recommended vitamin D RDA for people 9-70 years was 600 IU with a maximum of 4000 IU.  I know many people whose physicians have recommended that they take 20,000 IU or more of vitamin D daily to treat either their osteopenia or “low” 25-OH vitamin D levels.  Crazy stuff

In summary, osteoporosis is a serious medical condition that can be caused in part by low calcium and/or vitamin D levels and that can predispose people to bone fractures.  Most people in the U.S. are not deficient in either calcium or vitamin D and can maintain normal levels just by eating well and maybe, getting sun exposure now and then.  If a person has a legitimate need for calcium and/or vitamin D supplementation, taking the supplements with food results in better absorption than if taken on an empty stomach.  Physicians would do well to read the recent Institute of Medicine report on vitamin D and calcium supplementation.