Literature Review and Commentary

by Alan R. Gaby, MD

Vitamin Dosage for HIV Patients

Some 3418 Tanzanian patients in with human immunodeficiency virus (HIV) infection who were initiating highly active antiretroviral therapy (HAART) were randomly assigned to receive, in double-blind fashion, high doses or standard doses of vitamins C, E, and B complex for 2 years. The daily dosages were thiamine (1.2 vs. 20 mg), riboflavin (1.2 vs. 20 mg), vitamin B6 (1.3 vs. 25 mg), niacin (15 vs. 100 mg), vitamin B12 (2.4 vs. 50 mcg), folic acid (0.4 vs. 0.8 mg), vitamin C (80 vs. 500 mg), and vitamin E (15 vs. 30 mg). The study was stopped early, after a median follow-up period of 15 months, because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement (relative risk = 1.44; 95% confidence interval, 1.11–1.87). At the time the trial was stopped, compared with standard doses, high doses had no effect on the risk of HIV disease progression or death, and had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin levels.

Comment

: Previous randomized controlled trials have shown that high-dose micronutrient supplementation can increase CD4 counts and reduce HIV disease progression and mortality among individuals not receiving HAART. However, the safety and efficacy of such supplementation has not been established in patients receiving HAART. The results of the present study suggest that higher doses of vitamins are no more effective than lower doses in patients receiving HAART, and that the higher doses may cause stress on the liver in some patients. While higher doses of vitamins might be more effective than lower doses for enhancing immune function, this potentially beneficial effect could be negated by an interference by one or more nutrients with the effects of the antiviral medications. For example, one study found that supplementation with 1000 mg per day of vitamin C decreased plasma indinavir concentrations in patients receiving indinavir as a component of HAART.

Isanaka S et al. Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial. JAMA. 2012;308:1535–1544.

Vitamin D and Inflammation

In a study of 2015 patients referred for coronary angiography, significant inverse correlations were found between serum levels of 25-hydroxyvitamin D and high-sensitivity C-reactive protein (CRP; a marker of inflammation), and between serum levels of 25-hydroxyvitamin D and neopterin (a marker for immune activation) (p < 0.0001 for each comparison).

Comment

: Low 25-hydroxyvitamin D concentrations are found in patients with various clinical conditions that are characterized by inflammation and immune activation. Therefore, it has been argued that these patients could benefit from vitamin D supplementation. However, there is evidence that serum 25-hydroxyvitamin D is not a reliable indicator of vitamin D status in people with inflammatory and autoimmune disorders. Randomized controlled trials of vitamin D supplementation in patients with these disorders have produced conflicting, but mostly negative, results.

Murr C et al. Vitamin D deficiency parallels inflammation and immune activation, the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Clin Chem Lab Med. 2012;50:2205–2212.

Danger of High-Dose Iodine During Pregnancy

Three infants in Portland, Oregon, were found on newborn screening to have congenital hypothyroidism. The mothers of the 3 infants had taken 12.5 mg per day of iodine (Iodoral) during pregnancy. Levels of whole-blood iodine in the newborn screening samples were 10 times above mean control values. The iodine content of the breast milk of 1 of the mothers was 18 times the upper limit of normal.

Comment

: Fetal and neonatal exposure to excessive amounts of iodine, through placental transfer or breast milk, can cause neonatal hypothyroidism by suppressing thyroid hormone production. In previous columns in the Townsend Letter, I have cautioned against the routine use of high-dose iodine, which has become popular among some practitioners. Based on these 3 case reports, high-dose iodine (such as more than several hundred micrograms per day) should be avoided during pregnancy.

Connelly KJ et al. Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion. J Pediatr. 2012;161:760–762.

Colon-Release Propionyl-L-Carnitine for Inflammatory Bowel Disease

Fourteen patients (aged 16–80 years; mean, 49 years) with mild-to-moderate ulcerative colitis (n = 10) or Crohn’s disease colitis with no known small-intestinal Crohn’s disease (n = 4), who were receiving stable therapy with oral aminosalicylates, mercaptopurine, or azathioprine for at least 8 weeks were treated with 1 g of orally administered colon-release propionyl-L-carnitine hydrochloride twice a day (1 hour before breakfast and 1 hour before dinner) for 4 weeks. Colonoscopy was performed before and immediately after the treatment period. Clinical response was defined as a decrease of at least 3 points in Disease Activity Index (DAI), and clinical remission was defined as a DAI score of 2 or less. Histological response was defined as an improvement of the histological index by at least 1 point. Seventy-one percent of the patients achieved clinical response (6 of 10 with ulcerative colitis and 4 of 4 with Crohn’s disease), and 64% achieved clinical remission (6 of 10 with ulcerative colitis and 3 of 4 with Crohn’s disease). Seventy-nine percent of the patients had a histological response; no patient showed histological worsening. The median DAI score improved by 71%. No side effects were reported.

Comment

: In a previous double-blind trial, colon-release propionyl-L-carnitine significantly increased the number of responders in patients with mild-to-moderate ulcerative colitis (72% vs. 50%; p = 0.02). The results of the new study confirm the efficacy of this treatment for ulcerative colitis, and suggest that it may also be effective for Crohn’s disease of the colon. Propionyl-L-carnitine presumably works by increasing mitochondrial energy production, which appears to be impaired in people with inflammatory colitis.

Merra G et al. Propionyl-L-carnitine hydrochloride for treatment of mild to moderate colonic inflammatory bowel diseases. World J Gastroenterol. 2012;18:5065–5071.

Whey Protein Triggers Acne

Five male patients (aged 14–18 years) developed acne (acne vulgaris) shortly after starting whey protein supplements. Three of the teenagers had used the supplement for muscle building and the other 2 had used it in an attempt to gain weight. All 5 patients had a poor response to conventional treatment, which included oral antibiotics, topical retinoids, and benzoyl peroxide. The lesions cleared in 4 patients after discontinuation of whey protein, and 1 patient had a recurrence after restarting the supplement. At least 6 different brands of whey protein had been used, including whey protein shakes and reconstituted powders.

Comment

: Previous studies have linked acne to the consumption of either whole or skim milk. The results of the present report suggest that whey protein may be the fraction of dairy products that promotes the development of acne.

Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes. Cutis. 2012;90:70–72.

Magnesium for Epilepsy

A retrospective chart review was conducted on 22 patients with drug-resistant epilepsy, in which magnesium supplementation had been tried empirically. Magnesium was given in most cases as magnesium oxide at a dosage of 420 mg (252 mg of elemental magnesium) 1 to 4 times per day. Mean seizure frequency (days per month) decreased by 33.3% (from 15.3 to 10.2) at the first follow-up (3 to 6 months) (p = 0.02) and by 49% (to 7.8) at the second follow-up (6 to 12 months; p = 0.004). Thirty-six percent of the patients had a reduction in seizure frequency of at least 75%, and 2 patients were seizure free. Most patients were well maintained on 252 mg of elemental magnesium twice a day without significant adverse effects, although 4 patients experienced diarrhea.

Comment

: Magnesium deficiency can cause seizures and can increase susceptibility to seizure-inducing stimuli. Parenteral magnesium is known to be an effective treatment for the seizures of neonatal tetany, and possibly for those associated with ethanol withdrawal. In previous research, magnesium concentrations in serum and cerebrospinal fluid were significantly lower in 40 patients with grand mal epilepsy than in controls. That finding suggests that some patients with epilepsy have suboptimal magnesium status. It appears from the current study that magnesium supplementation is beneficial for many patients with treatment-resistant epilepsy, although controlled trials are needed to confirm these preliminary observations. Because magnesium is inexpensive and relatively free of side effects, and because it does not seem to interact with anticonvulsant medications, magnesium supplementation should be considered for all epileptic patients.

Abdelmalik PA et al. Magnesium as an effective adjunct therapy for drug resistant seizures. Can J Neurol Sci. 2012;39:323–327.

Problems with Lab Test for Serum Vitamin B12

Frozen serum samples obtained 10 to 15 years previously from patients with untreated pernicious anemia were examined. Fifteen of the samples had anti–intrinsic factor antibodies and 8 did not. Aliquots were tested for vitamin B12 levels in 3 clinical laboratories with the use of different competitive-binding luminescence assays (CBLAs). The 3 CBLAs showed false-normal values in 6 of 23 (26%), 5 of 23 (22%), and 8 of 23 (35%) serum samples, respectively, as compared with a radioisotope-dilution assay (p = 0.03, p = 0.06, and p = 0.02, respectively). Five samples failed with all 3 CBLAs. False-normal results were found with 33-53% of serum samples that were positive for anti–intrinsic factor antibodies. In contrast, no sample that was negative for anti–intrinsic factor antibodies had a false-normal result (p = 0.01 to 0.06).

Comment

: During the past decade, the CBLA has replaced older microbiologic and radioisotope-dilution assays for vitamin B12 status. In 2000, a study showed that a CBLA frequently failed to detect low vitamin B12 levels; however, that study was disputed by the manufacturer. During the past 6 years, 5 case reports have identified false-normal vitamin B12 levels in 7 patients with pernicious anemia. It has been suggested that these incorrect measurements may be due to a failure of CBLAs to inactivate serum anti–intrinsic factor antibodies. CBLA brochures advise users to test for anti–intrinsic factor antibodies when they are uncertain about the reliability of a normal vitamin B12 test result. However, a much better solution would be for the manufacturers of the test kits to correct the problem, or for laboratories to use a more reliable assay method.

Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. N Engl J Med. 2012;367:385–386.

Dhea for Glucocorticoid-Induced Osteoporosis

Nineteen women (aged 50–78 years) who had been treated with prednisone for at least 3 years in average doses greater than 7.5 mg per day, who had a bone mineral density (BMD) T-score of less than −1.5 at the lumbar spine, and who could not tolerate bisphosphonates were studied. During the first year they received 400 to 800 mg per day of supplemental calcium (depending on dietary calcium intake) and 0.5 mcg per day of alphacalcidiol (a vitamin D analogue). Patients with hypercalciuria also received hydrochlorothiazide. During the second year, dehydroepiandrosterone (DHEA; 50 mg per day after breakfast) was added to the treatment regimen. After 6 weeks and again after 6 months, the DHEA dose was decreased to 25 mg per day if the serum DHEA-sulfate level was greater than 4000 ng/ml. After the first year, BMD of the lumbar spine and femoral neck decreased significantly compared with baseline. After the second year, compared with the end of the first year, significant increases were seen in BMD at both sites, and the values were approximately the same as at the start of the study.

Comment

: The adrenals glands are the main source of DHEA production in women. Treatment with glucocorticoids in dosages large enough to suppress adrenal function typically results in a marked decline in serum levels of DHEA and DHEA sulfate. Since DHEA has an anabolic effect on bone, glucocorticoid-induced osteoporosis might be due in part to the suppression of DHEA production. The results of the present study suggest that supplementation with DHEA can prevent osteoporosis in women being treated with glucocorticoids.

Papierska L et al. Effect of DHEA supplementation on serum IGF-1, osteocalcin, and bone mineral density in postmenopausal, glucocorticoid-treated women. Adv Med Sci. 2012;57:51–57.