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Literature review & commentary.

Thiamine for Chronic Heart Failure

Nine diuretic-treated patients (aged 45-75 years) with symptomatic chronic heart failure and a left ventricular ejection fraction (LVEF) less than 40010 were randomly assigned to receive, in double-blind fashion, 300 mg per day of thiamine or placebo for 4 weeks. After a 6-week washout period, each patient received the alternate treatment for an additional 4 weeks. Eight patients were receiving a loop diuretic or thiazide diuretic and 4 were receiving an aldosterone antagonist. Mean LVEF at baseline was 29.5%. Mean LVEF was significantly higher after thiamine treatment than after placebo (32.8% vs. 28.8%; p = 0.024).

Comment: Patients with heart failure may be at increased risk for thiamine deficiency, as a result of malabsorption and advanced age. Diuretic treatment for heart failure increases urinary thiamine excretion, which can further decrease thiamine status. Thiamine deficiency can cause or exacerbate heart failure (beriberi heart disease). In the present study, thiamine supplementation improved LVEF in patients receiving diuretics for chronic heart failure. Thus, thiamine supplementation should be considered as part of a comprehensive treatment program for heart failure, particularly in patients who are receiving diuretics. Patients receiving thiamine should also be given magnesium, which is required for the conversion of thiamine to its biologically active form. Patients with heart failure are frequently deficient in magnesium. In patients who are deficient in both thiamine and magnesium, symptoms of thiamine deficiency may not respond to thiamine supplementation unless magnesium deficiency is also corrected. In addition, administration of large doses of thiamine can exacerbate magnesium deficiency.

Schoenenberger AW et al. Thiamine supplementation in symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled, cross-over pilot study. Clin Res Cardiol. 2012;101:159-164.

Acetyl-L-Carnitine for Cirrhosis

Sixty-seven patients (aged 34-67 years) with cirrhosis of the liver and minimal hepatic encephalopathy (the preclinical stage of overt hepatic encephalopathy) were randomly assigned to receive, in double-blind fashion, 2 g of acetyl-L-carnitine (ALC) twice a day or placebo for 90 days. Compared with placebo, ALC resulted in significant improvements in energy levels, general functioning and well-being, depression, and anxiety, and significant decreases in plasma levels of ammonia and bilirubin.

Comment: Hyperammonemia (increased serum ammonia levels) is responsible in part for many of the symptoms associated with cirrhosis. Carnitine concentrations in the liver and other tissues have been found to be low in patients with cirrhosis. Carnitine plays a role in urea synthesis, and has been shown to lower ammonia levels in patients with cirrhosis. ALC serves as a source of L-carnitine and also functions as a cholinergic neurotransmitter. In the present study, ALC improved both physical and mental symptoms in cirrhotic patients with minimal hepatic encephalopathy.

Malaguarnera M et al. Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Scand I Gastroentera 2011;46:750-759.

Fish Oil for Pregnant Women

Some 2399 pregnant women (mean age, 29 years) of less than 21 weeks of gestation were randomly assigned to receive, in double-blind fashion, 1500 mg per day of docosahexaenoic acid (DHA)-enriched fish oil (providing 800 mg per day of DHA) or placebo until delivery. The incidence of gestational diabetes was nonsignificantly lower by 3% and the incidence of preeclampsia was nonsignificantly lower by 13% in the active-treatment group than in the placebo group. There were 12 perinatal deaths and 5 neonatal convulsions in the placebo group compared with 3 perinatal deaths and no neonatal convulsions in the active-treatment group (p = 0.03 for each comparison).

Comment: The results of this study suggest that supplementation with a modest dose of DHA-enriched fish oil can improve outcomes in the infant. The results are also consistent with the possibility that fish oil reduces the incidence of gestational diabetes and preeclampsia, although the reductions were small and not statistically significant. Interestingly, the authors of this study incorrectly concluded that DHA supplementation did not reduce the incidence of gestational diabetes or preeclampsia. The correct conclusion is that DHA supplementation resulted in small decreases in the incidence of gestational diabetes and preeclampsia, but because the reductions were not statistically significant, there is less than a 95% probability that the reductions were "real." Failure to demonstrate that an effect was statistically significant is not the same as proving that there was no effect.

Zhou SJ et al. Fish-oil supplementation in pregnancy does not reduce the risk of gestational diabetes or preeclampsia, Am J Clin Nutr. 2012;95:1378-1384.

Vitamin D and Depression

Among 54 Swedish children (mean age, 16 years; range, 10-19 years) with moderate or severe depression, the mean serum 25-hydroxyvitamin D (25[OH]D) concentration was 41 nmol/L, a level that is suggestive of vitamin D deficiency according to the current laboratory reference range. Six patients had a level less 25 nmol/L, which is suggestive of severe deficiency. All patients with a serum 25(OH) level less than 60 nmol/L were given 4000 IU per day of vitamin D for 1 month, then 2000 IU per day for 2 months. Patients also received psychotherapy, supportive counseling, and in some cases medication. Significant improvements were seen in measures of depression, irritability, tiredness, mood swings, sleep difficulties, and ability to concentrate.

Comment: Several previous studies have suggested that vitamin D has a positive effect on mood, although the results have been conflicting. 25(OH)D is an acute-phase reactant, which means that the level falls in response to inflammation. Since there is an inflammatory component to depression, the low 25(OH)D levels observed in the present study might be in part simply a reflection of the inflammatory process, rather than being indicative of low vitamin D status. In addition, it is not clear how much (if any) of the clinical improvement in the present study was due to vitamin D supplementation, since the patients also received other treatments for depression. Controlled trials are therefore needed to confirm this study.

Hogberg G et al. Depressed adolescents in a case-series were low in vitamin D and depression was ameliorated by vitamin D supplementation. Acta Paediatr. 2012;101:779-783.

Folic Acid and Cancer

This study examined the incidence of various types of cancer in the US in children aged 4 years or younger between 1986 and 2008. Folic acid fortification of grains was instituted in the US between 1996 and 1998. and postfortification incidence rates were similar for all cancers combined and for most specific cancer types. Rates of Wilms tumor, primitive neuroectodermal tumors, and ependymomas were significantly lower postfortification.

Comment: Concern has been raised in recent years that folic acid supplementation could increase the risk of certain types of cancer. However, the evidence has been conflicting, and the only studies that showed a potential adverse effect were post-hoc analyses of trials that were not originally designed to examine the effect of folic acid on cancer rates. Several studies (including the present one) have shown that folic acid fortification of grains has not been associated with an increased incidence of cancer. While the final answer awaits randomized controlled trials in which cancer incidence is a primary outcome measure, the available evidence suggests that the benefits of folic acid supplementation (such as prevention neural tube defects and strokes) outweigh the potential risks.

Linabery AM et al. Childhood cancer incidence trends in association with US folic acid fortification (1986-2008). Pediatrics. 2012;129:1125-1133.

Selenium and Coenzyme Q10 Decrease Cardiovascular Mortality

Four hundred forty-three elderly Swedish individuals (aged 70 to 88 years) were randomly assigned to receive, in double-blind fashion, 100 mg of coenzyme Q10 twice a day and 200 mcg per day of selenium or placebo for 5 years. Fifty-six percent of the participants in the active-treatment group and 47% of those in the placebo group completed the trial. In intent-to-treat analysis, during a follow-up period of 5.2 years, cardiovascular mortality was 53% lower in the active-treatment group than in the placebo group (5.9% vs. 12.6%; p = 0.015). Similar reductions in cardiovascular mortality were seen after exclusion of those who did not complete the trial, but the numbers were considered too small to perform a statistical analysis. The cardiac biomarker, N-terminal proBNP, was significantly lower (indicating better cardiac health) in the active-treatment group than in the placebo group (mean, 214 ng/L vs. 302 ng/L at 48 months; p = 0.014). Cardiac function, as determined by echocardiography, was significantly better in the active-treatment group than in the placebo group (p = 0.03).

Comment: Previous studies have shown that coenzyme Q10 and selenium each have beneficial effects on cardiovascular health. The present study demonstrated that long-term supplementation with both of these nutrients decreased cardiovascular mortality and improved cardiac function in elderly Swedish individuals. The soils in Sweden are low in selenium, and daily intake of selenium in that country is low (30-40 mcg per day), so the results of this study may not necessarily apply to other populations.

Alehagen U et al. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: A 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. Intl Cardiol. Epub 2012 May 22. )

N-Acetylcysteine for Autism

Thirty-three children (ages 3-11 years; 31 male, 2 female) with autistic disorder were randomly assigned to receive, in double-blind fashion, N-acetylcysteine (NAC) or placebo for 12 weeks. The dosage of NAC was 900 mg per day for 4 weeks, then 900 mg twice a day for 4 weeks, then 900 mg 3 times per day for 4 weeks. Compared with placebo, NAC resulted in a significant improvement on the Aberrant Behavior Checklist irritability subscale (p < 0.001). Side effects were mainly gastrointestinal; the incidence of these side effects was nonsignificantly higher in the NAC group than in the placebo group.

Comment: An imbalance in the excitatory/inhibitory neurotransmitter systems, with abnormalities in glutamatergic pathways, has been implicated in the pathophysiology of autism. In addition, chronic redox imbalance has been linked to autism. NAC is a glutamatergic modulator and an antioxidant, effects that might be of value in the treatment of autism. The results of the present study indicate that NAC improved irritability in children with autistic disorder.

Hardan AY et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012;71:956-961.

Strontium and Bone: Long-Term Effects

Postmenopausal women who had received 2 g per day of strontium ranelate (680 mg per day of elemental strontium) for 5 years as part of the double-blind Spinal Osteoporosis Therapeutic Intervention (SOTI) or Treatment of Peripheral Osteoporosis (TROPOS) trials were invited to continue the treatment for an additional 5 years in open-label fashion. Two hundred thirty-three women completed the 5-year extension trial, during which they received daily 2 g of strontium ranelate, 1000 day of calcium, and 400 to 800 IU of vitamin D. Over the total 10-year period, lumbar bone mineral density (BMD) increased continuously and significantly (p < 0.01 versus the previous year), with a 34.5% mean increase from baseline to 10 years and a 7.9% increase (relative to the baseline value) from year 6 to year 10. The incidences of new vertebral fractures (20.6% vs. 18.5%) and of any osteoporotic fracture (30.3% vs. 27.5%) were nonsignificantly higher in years 6-10 than in years 1 through 5. The incidence of new fractures was significantly lower in people receiving strontium ranelate than in a matched control group who had received placebo during the initial 5-year studies and who were followed for an additional 5 years.

Comment: During the original 5-year randomized controlled trials, the incidence of vertebral fractures was reduced by about 40% compared with placebo. The vertebral fracture rate was 12% higher during the 5-year extension phase than during the original trials, but the rate remained lower than that in an untreated control group. One could argue that the control group in the extension phase is not truly comparable to the women who took strontium ranelate for 10 years, because the women who chose to continue treatment may have been different from those who did not continue, and because the simple act of participating in a trial has been shown to improve outcomes. However, the fracture rate in the strontium group in years 6 to 10 was lower than that in the placebo group during years 1 to 5, which suggests that the efficacy of strontium persists at least in part for up to 10 years.

A point of concern is that in the strontium group, even though BMD continued to increase every year, the fracture rate was higher in years 6 to 10 than in years 1 to 5. Moreover, in the early years of the double-blind phase of the trials, the fracture-preventing effect of strontium tended to wane despite progressive increases in BMD. What these findings suggest is that some of the new bone formed during strontium treatment is not of high quality. In previous research, feeding high-dose strontium (1.5% of the diet or greater) to experimental animals caused mineralization defects that resembled rickets. As little as 0.19% dietary strontium (an amount similar to that used in the human research) caused hypomineralization and reduced the size of bone mineral crystals in young rats. It has been suggested that the deleterious effects of strontium supplementation were due to the concomitant feeding of a calcium-deficient diet. However, in the study in which 0.19% strontium caused bone abnormalities, the diet contained 0.5% calcium, which is the estimated calcium requirement for the growing rat, and which would be equivalent to more than 2000 mg of calcium per day for humans.

There is now strong evidence that high-dose strontium is useful for the prevention and treatment of osteoporosis. However, questions remain regarding what the optimal dosage is and how long it is safe to administer large doses. The potential for bisphosphonates to cause osteonecrosis of the jaw and atypical fractures of the femur was not discovered until these drugs had been on the market for many years. At present, one cannot rule out the possibility that adverse effects will also emerge in patients who have been on high-dose strontium for a decade or more.

Most of the research on strontium in humans has been done with strontium ranelate, a patented form of the mineral that is used in Europe as a prescription medicine. Several cases of severe adverse reactions (drug-induced hypersensitivity syndrome) have been reported in patients taking strontium ranelate. To my knowledge, no such adverse effects have been reported with the strontium salts that are used in the US (e.g., strontium citrate, strontium gluconate). While strontium ranelate is the only form of strontium that has been subjected to randomized controlled trials, there is no reason to assume that the other forms of strontium would be ineffective for osteoporosis prevention and treatment.

Reginster JY et al. Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis. Osteoporos Int. 2012;23:1115-1122.

by Alan R. Gaby, MD
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Title Annotation:thiamine for chronic heart failure; acetyl-L-carnitine for cirrhosis; fish oil for pregnant women
Author:Gaby, Alan R.
Publication:Townsend Letter
Geographic Code:1USA
Date:Dec 1, 2012
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