“I swear I had nothing to do with this!”
A short post today, for me at least, but an important one to file away for the next time somebody asks “What’s the harm?” during a discussion on the use of irregular medicine in the care of pediatric (or any) patients.
The case
The September 2015 issue of Pediatrics in Review, the official American Academy of Pediatrics source for continuing medical education, contains a case report that should be of particular interest to readers of Science-Based Medicine. The authors, pediatricians at Children’s Hospital at Albany Medical Center, describe the ordeal of a six-year-old boy, previously healthy except for eczema, suffering with lower extremity pain to the point of crying with attempts to walk or to even bear weight. For those of you who don’t have experience with children of this age, it takes a considerable amount of discomfort or disability to interfere with their determination to remain in a near constant state of motion. Refusal to bear weight is a red flag that we take very seriously as the cause in a young child is often serious, ranging from traumatic injuries and severe infections of the bones or joints to diagnostic dilemmas such as leukemia and juvenile rheumatoid arthritis.
In addition to his pain, which had been steadily worsening over the twelve days prior to seeking care at the authors’ facility, his family was concerned about his malaise (extreme fatigue), nausea, poor appetite, and unusually dry lips that were cracked and bleeding. A preliminary evaluation by his primary care pediatrician at the onset of his symptoms was reasonable, ruling out the more common possible etiologies, yet was ultimately unfruitful.
The eventual finding of a significantly elevated serum calcium level, as well as the overall presentation of his symptoms, was concerning for cancer but labs and imaging, including bone marrow biopsy, CT of the brain, and MRI of the spine, were normal. A nuclear medicine study called a bone scan revealed abnormally elevated uptake of technetium-99m in his long bones, which was a clue for a endocrine abnormality. This led to additional but also unhelpful laboratory tests.
Meanwhile, initial attempts to treat the child’s increased blood level of calcium with hydration and a medication that inhibits the indirect bone resorbing activity of parathyroid hormone failed. His calcium level, and thankfully his symptoms, did respond once he was treated with a bisphosphonate and a strong diuretic. Bisphosphonates bypass parathyroid hormone and directly inhibit the activity of osteoclasts, cells vital to the healthy maintenance of our bones and in regulating levels of important minerals in our blood. It’s not a commonly prescribed medication in kids.
The reveal
Although the patient was recovering, it appears that the team was at a loss until the child’s parents revealed a game-changing piece of information later in the admission. Six months before his pain and other worrisome symptoms began, they had sought treatment for his eczema from a “natural health practitioner.” He had been prescribed a number of supplements containing vitamin A, one with a whopping 39,000 IU per pill. He had vitamin A toxicity.
Vitamin A toxicity in a healthy child living in the United States is rare as hen’s teeth. I doubt that the team would have figured it out without the (better late than never) disclosure by the family. Even checking vitamin A levels in the blood, which would normally result in a discussion of which member of the genus Equus is most likely to be the source of audible hoofbeats, might not have led to a lucky catch because they don’t correlate well with tissue levels.
The recovery
The patient responded to medical management, cessation of his dangerous supplement regimen, and a diet that limited his calcium and vitamin D intake. His recovery was not easy, however, as he needed physical therapy for persistent weakness that lasted for months. During his hospitalization, he underwent numerous blood draws and aspiration of his bone marrow for testing. He was also exposed to significant amounts of ionizing radiation and likely required sedation for either his bone marrow biopsy, his spine MRI (which can take over an hour), or both. He was treated with medications having significant, although unlikely, potential side effects. All of this because some irresponsible and poorly-educated quack thought it appropriate to prescribe supplements to a young child.
Vitamin A, what is it good for?
Vitamin A is an interesting chemical, and one traditionally associated with vision in the minds of the public and medical professionals. The ancient Egyptians first made the association between improved vision at night and eating animal liver but Swiss researchers first isolated and named vitamin A. We now recognize two primary forms of the compound: provitamin A carotenoids found in green leafy vegetables and carrots, beta-carotene being the only one metabolized by mammals, and the more active preformed vitamin A found in animal sources such as liver and egg yolk. Preformed vitamin A compounds, such as retinol and retinoic acid, are also typically used in drugs and supplements like the ones taken by the poor victim in the above case.
Provitamin A, even when ingested in large quantities, is generally felt to be incapable of causing toxicity. Our bodies must convert beta-carotene into active vitamin A, a process which is tightly regulated such that intake above a certain level causes a negative feedback inhibition. I once cared for a young infant who was being fed only 100% carrot juice because of religious beliefs pertaining to proper nutrition. The diffusely edematous and orange infant had a severe deficit in protein despite adequate calories, a condition known as kwashiorkor, but did not suffer any ill effects related to excessive vitamin A intake. Animal or synthetic sources of preformed vitamin A on the other hand are already highly active and can easily lead to toxic effects because there is no mechanism of feedback inhibition.
Vitamin A plays an important role in numerous biological functions, with vision being the most well known. Appropriate levels of vitamin A prevent pathologic dryness of the eye and surrounding tissues, a condition known as xerophthalmia, which is a leading cause of preventable blindness in developing countries. Vitamin A is also pivotal in the process of phototransduction, the conversion of light into electrical signals to the brain. Two photoreceptor cells, rods (motion and nightvision) and cones (light and color vision in bright light), require derivatives of vitamin A for proper function. Vitamin A is also important in cell health and growth, particularly in the skin and bone marrow, as well as immunity, bone metabolism, reproduction, and prenatal development.
Deficiency of vitamin A isn’t something we deal with much in the United States and other developed nations, although conditions that can result in poor absorption of fat, such as cystic fibrosis and Crohn’s disease, put some patients at risk. Sadly, deficiency is far from a rarity in the rest of the world where each year half a million infants and toddlers lose their vision because of a lack of dietary sources. Many of these children die. Efforts at providing supplementation to at-risk children are ongoing, but there are misinformed activists fighting against our most promising advances in the prevention of blindness and death in resource-poor regions.
Too much of a good thing
Excessive vitamin A intake leading to toxicity is also rare, and is likely even less common than deficiency in developed countries although data on prevalence is lacking. There are no disease states that predispose patients to toxicity. As stated earlier, we get vitamin A from our diet in the form of certain plants (provitamin A) and animal products (preformed vitamin A), but it is difficult to overdose through diet. It isn’t impossible though. Vitamin A is primarily stored in the liver, and consumption of that organ harvested from some animals, such as polar bears and seals, can cause severe acute illness and even death.
How much vitamin A we should get daily is a bit complicated because it depends on where it comes from. A much smaller amount of preformed vitamin A from animal organs or supplements is acceptable compared to a relatively large amount of plant-derived beta-carotene, which must be converted to an active form. Just giving an amount in international units (IU) can be confusing if you don’t know the source. Daily allowances are usually measured in micrograms of retinol activity equivalents (RAE) that take into account biologic activity. Since beta-carotene really never leads to toxicity, we only have to worry about preformed compounds that come in supplements and drugs.
Toxicity, when it occurs, usually results after the ingestion of vitamin supplements containing amounts well above the recommended intake for long periods of time. Although the amount that will consistently result in symptoms is variable from person to person, as expected it takes less to cause damage in children than in adults. Daily intake of 3,000 IU or 900 micrograms RAE is considered the upper limit for safe daily intake in a 6-year-old child. Intake of 1,500 IU/kg body weight of preformed vitamin A (recommended daily allowance would be around 1,000 IU total in kids if all they got was the preformed compound) would be very likely to lead to toxicity in our patient, who received almost 2,000 IU/kg every day for six months from his bogus eczema treatment.
Acute toxicity can cause nausea and vomiting, dizziness, and blurry vision. Severe cases can result in effects on the central nervous system with resulting excessive tiredness and headache. The skin is also often involved in acute toxicity, becoming dry, sometimes painfully so, with cracked lips that can bleed. Longer term excess intake tends to affect the liver, bone, brain, and muscle leading to a variety of impairments including the presentation seen in the above case.
Vitamin A for eczema?
Vitamin A does play a role in the health of our skin. A deficiency can cause overgrowth of the outer layer of the skin and loss of hair follicles. But it doesn’t cause eczema. And even if it did, deficiency is extremely rare here in the United States.
Extremely high oral doses of chemicals closely related to vitamin A called retinoids are frequently used to treat severe cystic acne and psoriasis. Although the mechanism of action isn’t fully understood, the hypothesis is that the retinoids induce the death of sebaceous glands and a reduction in the amount of sebum, an oily secretion believed to play a large role in the pathophysiology of acne. The side effect profile of these medications is rough and as expected includes extremely dry and fragile skin. It is, essentially, purposeful and controlled vitamin A toxicity.
The use of megadoses of vitamin A to treat eczema, an allergic condition infamous for its pathologically dry and irritated skin manifestations, is absurd and potentially very dangerous. High-dose topical formulations of vitamin A derivatives, such as Retin-A, are also used to treat acne and can also cause severe skin reactions that would mimic and certainly exacerbate existing eczema. And there is no good evidence to support even the use of lower dose vitamin A-containing moisturizers for eczema in children.
Yet there are multiple online “resources” recommending the use of vitamin A for eczema, such as this nonsense from a nutraceutical company informed by a “team of naturopathic physicians.” WebMD lists eczema as a condition treated with vitamin A as well. And Orthomolecular Hall of Fame member Patrick Holford BSc, DipION, FBANT, NTCRP (I kid you not) loves vitamin A for eczema. There are so many more but I’ll stop there.
Conclusion: Harmful nonsense is harmful
There is a reason why Science-Based Medicine comes down so hard on practitioners of alternative medicine. And naturally we are particularly concerned about those who feel that they have the expertise to care for pediatric patient. This case is a perfect example.
Young children don’t have the ability to understand the complex variables involved in healthcare decisions and are helpless when their caregivers make poor choices based on misinformation and unscientific world views. This child should not have had to go through such an ordeal because there should not have been a “natural health practitioner” allowed to take part in his care. Unfortunately, fixing that problem is an uphill if not unwinnable battle so we must focus instead on education of the public and the prevention or removal of legislation that places children at greater risk.