Literature Review and Commentary

By Alan R. Gaby, MD

Contents

1. Coenzyme Q10 decreases plasma lipoprotein(a) concentrations

2. How much sodium should patients with heart failure consume?

3. Cooking methods influence insulin sensitivity

4. Nutritional supplement promotes “healthy aging”

5. Elderberry decreases severity of colds

6. Does fructose “shock” the liver?

7. Lab testing does not predict who will respond to vitamin B12 therapy

8. High-dose biotin interferes with thyroid testing

Coenzyme Q10 Decreases Plasma Lipoprotein(a) Concentrations

A meta-analysis was conducted on 7 randomized controlled trials (including a total of 409 subjects) that examined the effect of coenzyme Q10 (CoQ10) in doses of 100 to 300 mg per day for 4 to 12 weeks on plasma lipoprotein(a) levels. In the pooled analysis, compared with controls, CoQ10 supplementation resulted in a slight but significant decrease in the mean lipoprotein(a) level (weighted mean difference, −3.54 mg/dl; p < 0.001). CoQ10 had no effect on cholesterol or triglyceride levels.

Comment

: Lipoprotein(a) (Lp[a]) consists of a low-density lipoprotein (LDL) molecule bound by a disulfide linkage to a glycoprotein, apolipoprotein(a). Many, though not all, studies have found that an elevated serum Lp(a) concentration is an independent risk factor for cardiovascular disease. Although this association does not prove causality, there is evidence that Lp(a) is atherogenic. The results of this meta-analysis suggest that CoQ10 may be useful for cardiovascular disease prevention in people with elevated Lp(a) levels.

Sahebkar A et al. Supplementation with coenzyme Q10 reduces plasma lipoprotein(a) concentrations but not other lipid indices: A systematic review and meta-analysis. Pharmacol Res. 2016;105:198–209.

How Much Sodium Should Patients with Heart Failure Consume?

Data were analyzed from the multihospital Heart Failure Adherence and Retention Trial, which enrolled 902 symptomatic patients with heart failure (New York Heart Association class II/III) and followed them for a median duration of 36 months. After adjustment for characteristics that would lead to advice to restrict sodium intake, sodium restriction (< 2500 mg per day), as compared with higher sodium intake, was associated with a significantly higher incidence of the composite end point of death or hospitalization for heart failure (42.3% vs. 26.2%; hazard ratio [HR] = 1.85; p = 0.004). Exploratory subgroup analyses suggested that sodium restriction was associated with an increased risk of death or hospitalization for heart failure in patients not receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (HR = 5.78; p = 0.002).

Comment

: It is generally accepted that sodium restriction is an important component of the management of heart failure. However, the results of the present study suggest that severe sodium restriction may have deleterious effects, particularly in patients who are not receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Sodium deficiency can cause insulin resistance, hypotension, and other adverse effects. People taking sodium-depleting drugs such as loop diuretics (which are frequently used to treat heart failure) may be particularly susceptible to developing sodium deficiency on a low-salt diet. While salt restriction continues to be important for most patients with heart failure, moderate sodium intake may be preferable to severe sodium restriction in some cases.

Doukky R et al. Impact of dietary sodium restriction on heart failure outcomes. JACC Heart Fail. 2016;4:24–35.

Cooking Methods Influence Insulin Sensitivity

Twenty healthy overweight individuals (mean age, 34 years) were randomly assigned to receive, in double-blind fashion, isocaloric and macronutrient-matched diets that were high or low in advanced glycation end products (AGEs) for 2 weeks. After a 4-week washout period, each person consumed the alternate diet for an additional 2 weeks. At the beginning and end of each dietary period, insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp technique. Compared with the high-AGE diet, the low-AGE diet significantly increased insulin sensitivity.

Comment

: AGEs are formed during cooking of food by a reaction between a reducing sugar (glucose, fructose, or lactose) and a protein or an amine-containing lipid. AGEs are absorbed from food intact and persist in tissues, where they can modify protein structures. Consumption of AGEs is known to promote inflammation. The results of the present study indicate that AGEs also increase insulin resistance. These two effects of AGEs might explain in part why these compounds appear to play a role in the pathogenesis of cardiovascular disease, diabetic complications, and fibromyalgia.

Cooking at lower temperatures and in the presence of water results in less AGE formation compared with cooking at higher temperatures and in the absence of water. Temperature and cooking method seemed to be a more important factor for AGE formation than cooking time. Emphasizing boiling, poaching, and stewing over frying, broiling, and roasting may decrease daily AGE intake by up to 50%.

De Courten B et al. Diet low in advanced glycation end products increases insulin sensitivity in healthy overweight individuals: a double-blind, randomized, crossover trial. Am J Clin Nutr. 2016;103:1426–1433.

Nutritional Supplement Promotes ‘Healthy Aging’

This study’s investigated “healthy aging” in older French adults 5 years after the completion of the SU.VI.MAX study. In that double-blind trial, participants received a daily combination of vitamin C (120 mg), beta-carotene (6 mg), vitamin E (30 mg), selenium (100 µg), and zinc (20 mg) or placebo from 1994 to 2002. “Healthy aging” was assessed in 2007–2009 by using multiple criteria, including the absence of major chronic diseases and good physical and cognitive functioning. Data from a subsample of 3966 subjects (mean age of 65.3 years in 2007-2009) who were initially free of major chronic diseases were used to calculate relative risks. As compared with placebo, nutrient supplementation was associated with a greater probability of healthy aging among men (relative risk [RR] = 1.16; 95% confidence interval [CI], 1.04–1.29) but not among women (RR = 0.98; 95% CI, 0.86–1.11).

Comment

: The results of this study suggest that supplementation with moderate amounts of antioxidant nutrients (similar to amounts provided by a balanced diet rich in fruits and vegetables) may promote healthy aging in men. The results might have been even better if other nutrients had been included in the supplement. In particular, the magnesium content of many Western diets is low, and magnesium plays a key role in cardiovascular disease prevention. In addition, long-term use of zinc supplements may deplete copper, another important cardioprotective nutrient. Thus, it would have been desirable to include 1 to 2 mg per day of copper in the supplement, in order to balance the 20 mg per day of zinc.

Assmann KE et al. Healthy aging 5 years after a period of daily supplementation with antioxidant nutrients: a post hoc analysis of the French randomized trial SU.VI.MAX. Am J Epidemiol. 2015;182:694–704.

Elderberry Decreases Severity of Colds

Three hundred twelve individuals flying from Australia to an overseas destination were randomly assigned to receive, in double-blind fashion, 600 mg per day of an elderberry extract (Sambucus nigra L.; standardized to contain 22% polyphenols and 15% anthocyanins) or placebo. Treatment was begun 10 days prior to the flight. The dosage was increased to 900 mg per day on the day before the flight, and that dose was continued for 4 to 5 days after arrival at the destination. Compared with placebo, the elderberry extract decreased the number of colds by 29% (p = 0.2), the total number of days with cold symptoms by 52% (p = 0.05), and mean symptom severity by 58% (p = 0.05).

Comment

: Elderberry has been used traditionally for respiratory infections, and clinical trials have confirmed its efficacy (in combination with raspberry extract) in the treatment of influenza. In the present study, administration of an elderberry extract to air travelers decreased the number of days with cold symptoms, decreased symptom severity, and possibly decreased the incidence of colds.

Tiralongo E et al. Elderberry supplementation reduces cold duration and symptoms in air-travellers: a randomized, double-blind placebo-controlled clinical trial. Nutrients. 2016;8:E182.

Does Fructose ‘Shock’ the Liver?

An unspecified number of healthy males (mean age, 24 years; mean body mass index, 25 kg/m²) were studied. Following an overnight fast, each subject consumed a drink containing 75 g of fructose. Hepatic adenosine triphosphate (ATP) reserves (measured by ³¹P magnetic resonance spectroscopy) declined significantly by about 20% (p < 0.01) from baseline, reaching a nadir at 50 minutes, and recovering thereafter.

In previous studies, intravenous administration of fructose at a dose of 62.5 mg per kg of body weight (equivalent to 4.4 g for a 70 kg person) resulted in a transient decrease in hepatic ATP levels. People with obesity-related nonalcoholic fatty liver disease recovered more slowly from fructose-induced hepatic ATP depletion than did healthy age- and sex-matched controls. The present study is the first to demonstrate that oral administration of fructose can also deplete hepatic ATP. Repeated episodes of fructose-induced hepatic ATP depletion could conceivably lead to progressive liver injury. The results of the present study support other research that suggests that excessive fructose consumption is one of the contributing factors to the modern epidemic of nonalcoholic fatty liver disease.

Bawden SJ et al. Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A (31)P MRS study. Clin Nutr. 2016;35:645–649.

Lab Testing Does Not Predict Who Will Respond to Vitamin B12 Therapy

The author of this report reviewed the records of 78 patients with neuropathies who were treated with vitamin B12 orally (2 mg per day) or intramuscularly (1 mg 3 times a week for 2 weeks, then weekly for 8 weeks, then monthly). Sixty-five patients improved, including 35 who had other known causes of neuropathy. Pretreatment circulating levels of vitamin B12, methylmalonic acid (MMA), and homocysteine were normal in 72%, 33%, and 54% of vitamin B12 responders, respectively, and all 3 values were normal in 23% of responders. Moreover, vitamin B12 therapy did not significantly decrease elevated MMA and homocysteine levels in 20% and 37%, respectively, of responders tested, but it did decrease both metabolites in 75% of evaluable nonresponders. Oral vitamin B12 was effective for some patients, but the addition of parenteral vitamin B12 improved the response in 4 of these patients.

Comment

: The results of this study indicate that neuropathies frequently respond to vitamin B12 even in patients who have other known causes of neuropathy. Moreover, measuring circulating levels of vitamin B12, MMA, and homocysteine is not useful for identifying which patients are likely to respond to vitamin B12 therapy. Based on these observations, a therapeutic trial of vitamin B12 should be considered for all patients with neuropathies, even if they are not vitamin B12 deficient according to standard laboratory tests.

Solomon LR. Vitamin B12-responsive neuropathies: A case series. Nutr Neurosci. 2016;19:162–168.

High-Dose Biotin Interferes with Thyroid Testing

Six children receiving large doses of biotin (2–15 mg per kg of body weight per day) for the treatment of inherited metabolic diseases were found on routine examination to have laboratory results indistinguishable from those seen in Graves’ disease: elevated levels of free thyroxine (T4) and total triiodothyronine (T3), low levels of thyroid-stimulating hormone (TSH), and elevated levels of anti-TSH receptor antibodies. A literature search revealed that biotin may interfere with commonly used thyroid function tests. After discontinuation of biotin, thyroid hormone (T4 and T3) and TSH levels became normal after 24 to 48 hours and levels of anti-TSH receptor antibodies became normal within 7 days.

Comment

: The results of this study indicate that supplementation with large doses of biotin can interfere with the results of standard tests for thyroid function, potentially leading to an erroneous diagnosis of hyperthyroidism secondary to Graves’ disease. This misdiagnosis could result in the use of antithyroid medications, with deleterious consequences. A recent study suggested that treatment with 100 to 300 mg per day of biotin (1.4–4.3 mg per kg per day for a 70 kg person) can improve symptoms in patients with multiple sclerosis. People taking these large doses of biotin who need to have their thyroid function tested should discontinue biotin before having the tests.

Kummer S et al. Biotin treatment mimicking Graves’ disease. N Engl J Med. 2016;375:704–706.