Alan R. Gaby, MD
Omega-3 Fatty Acid Improves Outcomes in Acute Coronary Syndrome
Two hundred forty-one patients with acute coronary syndrome (myocardial infarction or unstable angina) were randomly assigned to receive 2 mg per day of pitavastatin with or without (control group) 1800 mg per day of eicosapentaenoic acid (EPA), begun within 24 hours after percutaneous coronary intervention. The primary endpoint was cardiovascular events occurring within one year, including death from a cardiovascular cause, nonfatal stroke, nonfatal myocardial infarction, and revascularization. The incidence of the primary endpoint was 54% lower (9.2% vs. 20.2%; p = 0.02) and cardiovascular disease-related mortality was 81% lower (0.8% vs. 4.2%; p = 0.04) in the EPA group than in the control group.
Comment: The results of this study indicate that the addition of EPA to a statin drug, as compared with a statin drug alone, decreased the incidence of cardiovascular events after percutaneous coronary intervention in patients with acute coronary syndrome. Possible mechanisms by which EPA was beneficial include an anti-inflammatory effect and inhibition of platelet aggregation.
Nosaka K, et al. Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study. Int J Cardiol. 2017;228:173-179.
Disaccharidase Deficiencies in Children with Chronic Abdominal Pain
Of 203 children (mean age, 11.5 years) with chronic abdominal pain who presented to the gastroenterology clinic at Children’s Hospital of Wisconsin, the proportion with abnormally low disaccharidase levels in small-intestinal biopsy samples was 37% for lactase, 21% for sucrase, 25% for glucoamylase (which cleaves glucose from maltose or starch), and 8% for palatinase (sucrase-isomaltase). Thirty-nine percent of the children with low lactase also had low sucrase, and 67% of those with low sucrase also had low lactase.
Comment: Lactose, sucrose, maltose, and isomaltose are the major disaccharides present in the human diet. These non-absorbable disaccharides are hydrolyzed to absorbable monosaccharides by disaccharidase enzymes present in the small-intestinal mucosa. It is well known that malabsorbed lactose is fermented by intestinal bacteria, which leads to the production of gases that can cause various gastrointestinal symptoms. Individuals with lactase deficiency often experience an improvement in various gastrointestinal symptoms when they avoid cow’s milk and other lactose-containing foods. Similarly, people with congenital sucrase deficiency experience an improvement in gastrointestinal symptoms when they avoid sucrose-containing foods.
In the present study, disaccharidase deficiencies were found to be common in children with chronic abdominal pain. In lieu of a small-bowel biopsy, a therapeutic trial of restricting dietary intake of lactose, sucrose, maltose, and isomaltose may relieve symptoms in some cases. After clinical improvement occurs, gradual reintroduction of disaccharides might help the patient determine which disaccharides they can tolerate and at what level of intake. Information on how to consume a low-disaccharide diet is available on the Internet.1
El-Chammas K, et al. Disaccharidase deficiencies in children with chronic abdominal pain. JPEN J Parenter Enteral Nutr. 2017;41:463-469.
Does Too Much Folic Acid or Vitamin B12 Cause Autism?
The Boston Birth cohort is a longitudinal prospective cohort study of 1,391 low-income urban, primarily minority mother-child pairs at the Boston Medical Center. Maternal multivitamin supplementation (3 to 5 times a week) was associated with a significantly lower risk of autism spectrum disorder (ASD) across all trimesters (adjusted hazard ratio [HR] = 0.33, 0.38, and 0.43 for 1st, 2nd, and 3rd trimesters, respectively). However, high levels of maternal plasma folate (> 59 nmol/L; HR = 2.27; p = 0.007) and vitamin B12 (> 600 pmol/L; HR = 3.01; p = 0.001) were associated with an increased risk of ASD. The greatest risk was in children of mothers who had high levels of both folate and vitamin B12 (HR = 17.6; p < 0.001).
Comment: A superficial interpretation of this research might be that taking a multivitamin during pregnancy can prevent ASD, but that taking too much folic acid or vitamin B12 can increase the risk of developing ASD. This study was widely reported in the media, and many reporters concluded that taking a lot of folic acid or vitamin B12 during pregnancy may be harmful. However, the study was observational and therefore cannot prove causation. Unfortunately, neither the original study nor the media reports provided any data (or even any speculation) on what dosages of these vitamins are beneficial and what dosages are harmful. One wonders how many pregnant women were frightened out of taking their multivitamin out of fear that it might contain too much folic acid or vitamin B12.
The likelihood is that the adverse associations reported in this study are spurious and do not imply a deleterious effect of folic acid or vitamin B12. The presence of a high serum folate concentration in a person who is not taking large doses of folic acid is a marker for small-intestinal bacterial overgrowth (SIBO), because some organisms that colonize the small intestine are capable of synthesizing folates.2,3 SIBO can cause deficiencies of many different nutrients, which could increase the risk of abnormal fetal brain development. Thus, high folate levels may be associated with an increased risk of ASD not because of any adverse effect of folate, but because of the association of high folate levels with SIBO. Similarly, an elevated vitamin B12 level is seen in people with liver disease,4 and even subtle liver dysfunction during pregnancy has the potential to cause adverse outcomes in the child.
Folic acid supplementation during pregnancy has clearly been shown to prevent neural tube defects. For women who have had a previous child with a neural tube defect, the Centers for Disease Control and Prevention (CDC) recommends a relatively large dose of folic acid (4,000 μg per day). Nothing about the present study should dissuade these women from following the CDC guidelines.
Raghavan R, et al. Maternal plasma folate, vitamin B12 levels and multivitamin supplementation during pregnancy and risk of autism spectrum disorder in the Boston Birth Cohort. Experimental Biology 2016 Meeting.
Does Exposure to Phthalates Promote Uterine Fibroids and Endometriosis?
Myometrial and leiomyoma (uterine fibroid) cells obtained from women with uterine fibroids were exposed to di-(2-ethylhexyl)-phthalate (DEHP) in vitro. Exposure to DEHP led to increased viability and increased expression of proliferating cell nuclear antigen and type I collagen in myometrial and leiomyoma cells. The urinary concentration of mono-(2-ethyl-5-carboxypentyl) phthalate was higher (p < 0.03) in women with uterine fibroids than in controls who had undergone a uterine surgical procedure but who did not have fibroids.
In another report, exposure of endometrial cells to DEHP in vitro increased their proliferative activity. Oral administration of DEHP to mice that had been subjected to implantation of human endometrial tissue significantly increased the size of the endometrial implant. In a case-control study, the mean urinary concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis than in controls.
Comment: Phthalates are endocrine-disrupting chemicals that are widely used in plastics (including food wrappers), makeup, shampoo, soaps, paints, medical products, and some pesticides. Phthalate metabolites are detectable in more than 75% of people in the US. The results of the studies described above suggest that phthalate exposure may contribute to the pathogenesis of uterine fibroids and endometriosis.
Kim JH, et al. In vitro effects of phthalate esters in human myometrial and leiomyoma cells and increased urinary level of phthalate metabolite in women with uterine leiomyoma. Fertil Steril. 2017;107:1061-1069.e1.
Kim SH, et al. Possible role of phthalate in the pathogenesis of endometriosis: in vitro, animal, and human data. J Clin Endocrinol Metab. 2015;100:E1502-E1511.
Folic Acid and Psoriasis
The association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and psoriasis risk was investigated in 84 Turkish patients with psoriasis and 212 healthy controls. The frequency of both the MTHFR 677TT and A1298C (homozygous) genotypes was markedly higher in patients than in controls. The T allele of MTHFR 677 and the C allele of MTHFR 1298 were associated with a 12.4-fold and a 17.0-fold increase, respectively, in the risk of having psoriasis.
Comment: This study found strong associations between polymorphisms of the gene that encodes for MTHFR and the risk of having psoriasis. Other research in this area has been conflicting, ranging from the same strong association found in the present study to no association. MTHFR is involved in folate metabolism. If there are indeed abnormalities of folate metabolism in some patients with psoriasis, that might explain the clinical observation that administration of large doses of folic acid improves or resolves the skin lesions in many patients with psoriasis.
One practitioner treated 40 psoriatic patients with high-dose folic acid (usually 100 mg per day) in combination with 1,000 mg per day of vitamin C. About 60% of the patients had complete or near-complete resolution of lesions and an additional 20% had lesser degrees of improvement. Improvement was typically noticeable after one month, and the maximum level of improvement was seen after an average of 2.5 months. After the maximum level of improvement was achieved, patients usually received a maintenance dose of 25 mg per day of folic acid.5
Kilic S, et al. Possible association between germline methylenetetrahydrofolate reductase gene polymorphisms and psoriasis risk in a Turkish population. Clin Exp Dermatol. 2017;42:8-13.
Vitamin C Benefits Dialysis Patients
Twenty-two patients with chronic renal failure who were receiving maintenance hemodialysis and who had functional iron deficiency (defined as transferrin saturation < 30 % and ferritin > 100 µg/L) and erythropoietin requirements of at least 4000 U per hemodialysis session received oral vitamin C (250 mg per day) for three months. Iron supplements were not given. Among the 15 patients who completed the study, the median erythropoietin dose requirement fell by 15% (p = 0.01) and the mean hemoglobin concentration increased from 10.1 g/dl to 10.7 g/dl (p = 0.03). Among the seven patients who had a decrease in their erythropoietin dose requirement, the mean decrease was 33%.
Comment: Functional iron deficiency is a major cause of persistent anemia in dialysis patients and also contributes to a suboptimal response to erythropoietin. Vitamin C enhances the mobilization of iron and increases its bioavailability. In previous studies, high-dose intravenous vitamin C decreased erythropoietin requirements and improved hemoglobin levels. The results of the present study suggest that a relatively low dose of oral vitamin C can also reduce erythropoietin requirements. In patients with renal failure, large doses of vitamin C can increase the deposition of oxalate in soft tissues, with potentially serious consequences. Low-dose vitamin C is therefore preferable to high-dose vitamin C in such patients. Erythropoietin is an expensive drug, so any low-cost treatment that can decrease erythropoietin requirements would reduce the overall cost of treatment in patients on hemodialysis.
Sultana T, et al. Oral vitamin C supplementation reduces erythropoietin requirement in hemodialysis patients with functional iron deficiency. Int Urol Nephrol.2016;48:1519-1524.
Levothyroxine: A Less-Than-Optimal Treatment for Hypothyroidism
A cross-sectional study was conducted on 9,981 participants in the US National Health and Nutrition Examination Survey (2001-2012) who had normal TSH levels. Participants using levothyroxine were compared with controls matched for age, sex, race, and serum TSH. The mean serum concentrations of total T4 (9.14 vs. 8.08 µg/dl) and free T4 (0.94 v. 0.80 ng/ml) were significantly higher, and the mean serum concentrations of total T3 (97.6 vs. 108.3 ng/ml) and free T3 (2.85 vs. 3.01 pg/ml) were significantly lower in people taking levothyroxine than in controls. Compared with controls, participants taking levothyroxine had a 15-20% lower mean serum T3:T4 ratio. Mean TSH levels were similar between groups. Compared with controls, levothyroxine-treated participants had higher body mass index (p < 0.001) despite consuming fewer calories per kg of body weight and were more likely to be taking beta-blockers (p < 0.0001), statins (p < 0.01), and antidepressants (p < 0.01).
Comment: These results indicate that people taking levothyroxine, as compared with matched controls, had lower serum T3:T4 ratios and had certain features consistent with possible hypothyroidism, despite having normal TSH levels. While the human thyroid gland secretes both levothyroxine and triiodothyronine (T3), the conventional approach to treating hypothyroidism is to administer levothyroxine by itself. The assumption upon which this approach is based is that the body converts levothyroxine to triiodothyronine in the exact amounts that are needed. The altered T3:T4 ratio seen in this study in levothyroxine-treated patients suggests that this assumption is not correct. Previous research and extensive clinical experience suggest that preparations containing both levothyroxine and triiodothyronine are more effective than levothyroxine alone for many hypothyroid patients.
Peterson SJ, et al. Is a normal TSH synonymous with “euthyroidism” in levothyroxine monotherapy? J Clin Endocrinol Metab. 2016;101:4964-4973.
Vitamin D in Heart Failure: Mixed Results
Two hundred twenty-nine patients (mean age, 69 years) with heart failure (New York Heart Association class II or III), a left ventricular ejection fraction (LVEF) of 45% or lower (mean, 26.1%), and a serum 25-hydroxyvitamin D level below 20 ng/ml (mean, 14.9 ng/ml) were randomly assigned to receive, in double-blind fashion, 4,000 IU per day of vitamin D3 or placebo for one year. The primary endpoint was the change in six-minute walk distance between baseline and 12 months. The mean six-minute walk distance decreased by 12.6 meters in the vitamin D group and increased by 10.1 meters in the placebo group (p = 0.26 for the difference in the change between groups). Mean LVEF (a secondary endpoint) increased by 7.65% in the vitamin D group and by 1.36% in the placebo group (p < 0.0001for the difference in the change between groups). In addition, compared with placebo, vitamin D resulted in a significant reversal of left ventricular remodeling (a secondary endpoint; indicating an improvement in left ventricular structure).
Comment: In this study of patients with heart failure and low 25-hydroxyvitamin D levels, vitamin D supplementation for one year resulted in a trend toward worse aerobic capacity but a significant improvement in physiological parameters (LVEF and left ventricular structure). Thus, the overall effect of vitamin D in this patient population is unclear. Longer-term studies may be needed to determine the effect of vitamin D supplementation on more clinically important endpoints such as mortality and frequency of hospitalization.
Witte KK, et al. Effects of vitamin D on cardiac function in patients with chronic HF: The VINDICATE study. J Am Coll Cardiol. 2016;67:2593-2603.
This article was originally published in Townsend Letter, December 2017.
References
1. Breaking the Vicious Cycle. http://www.breakingtheviciouscycle.info/legal/listing. Accessed August 31, 2017.
2. Camilo E, et al. Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology. 1996;110:991-998.
3. Shah HN, et al. Constipation in patients with thiamine deficiency after Roux-en-Y gastric bypass surgery. Digestion. 2013;88:119-124.
4. Arendt JFB, Nexo E. Unexpected high plasma cobalamin: proposal for a diagnostic strategy. Clin Chem Lab Med. 2013;51:489-496.
5. Elson B. Personal communication. June 9, 2002. A more detailed description of Elson’s protocol is described in Gaby AR. Psoriasis. In Gaby AR. Nutritional Medicine, Second Edition. Concord, NH, 2017; www.doctorgaby.com, chapter 192.
Published January 13, 2024
About the Author
Alan R. Gaby, M.D., is the author of the textbook, Nutritional Medicine, which is now in its third edition (doctorgaby.com). He received his undergraduate degree from Yale University, his M.S. in biochemistry from Emory University, and his M.D. from the University of Maryland. He was in private practice for 19 years, specializing in nutritional medicine. Over the past 43 years, Dr. Gaby has developed a computerized database of more than 29,000 individually chosen medical journal articles related to the field of natural medicine. He was professor of nutrition and a member of the clinical faculty at Bastyr University in Kenmore, Washington, from 1995 to 2002.
He is past president of the American Holistic Medical Association and gave expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. He is the author of Preventing and Reversing Osteoporosis (Prima, 1994), The Doctor’s Guide to Vitamin B6 (Rodale Press, 1984), and co-author of The Patient’s Book of Natural Healing (Prima, 1999). He was Chief Science Editor for Aisle 7 (formerly Healthnotes, Inc.) and has appeared on the CBS Evening News and the Donahue Show.