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From the Townsend Letter
April 2014

Literature Review & Commentary
by Alan R. Gaby, MD
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Probiotics for Nonalcoholic Fatty Liver Disease
A meta-analysis was conducted on 4 randomized controlled trials, including a total of 134 patients, that examined the effect of probiotic supplements on nonalcoholic fatty liver disease (NAFLD). In the pooled analysis, probiotics significantly decreased alanine aminotransferase (ALT) and aspartate transaminase (AST) levels and significantly improved insulin resistance, as measured by homeostasis model assessment. These results suggest that probiotics can decrease liver inflammation and improve glucose metabolism in patients with NAFLD.
Comment: NAFLD is a common condition in the US in both children and adults. It is characterized by hepatic steatosis (fat accumulation in the liver) that cannot be attributed to excessive alcohol consumption. Many patients with hepatic steatosis also have chronic hepatitis, in which case the condition is called nonalcoholic steatohepatitis (NASH). NAFLD is often asymptomatic, but it can progress to cirrhosis, particularly in patients with NASH. The cause of NAFLD is multifactorial, and risk factors include obesity and type 2 diabetes. Consumption of excessive amounts of fructose may also promote the development of NAFLD and NASH, as discussed below.
Animal studies suggest that NAFLD may be caused in part by microbial translocation (the movement of bacteria or bacterial products such as endotoxin across the intestines into the lymphatics or the visceral circulation). The beneficial effect of probiotics might be explained by their capacity to prevent the proliferation of pathogenic bacteria in the intestinal tract.

Ma YY et al. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis. World J Gastroenterol. 2013;19:6911–6918.

Does Excessive Fructose Consumption Lead to Nonalcoholic Fatty Liver Disease?
Seventeen monkeys were fed ad libitum a low-fat, high-fructose (24% of calories) diet, while 10 other monkeys were fed ad libitum a low-fat, low-fructose (less than 0.5% of calories, with less than 3% of calories supplied as sucrose and glucose) diet. The duration of the feeding period was 0.3 to 7.0 years. In a second study, 10 monkeys were fed the high- or low-fructose diets described above for 6 weeks at caloric amounts required to maintain a stable weight. In the ad libitum study, monkeys fed the high-fructose diet developed hepatic steatosis in comparison with the control diet, and the extent of hepatic fat accumulation was related to the duration of feeding. Monkeys fed the calorically controlled high-fructose diet showed significant increases in biomarkers of liver damage, endotoxemia, and microbial translocation, although they did not develop hepatic steatosis.
Comment: Nonalcoholic fatty liver disease (NAFLD), described in the comment above, has become much more common in the past few decades. This increase in prevalence has coincided with higher fructose consumption, mainly in the form of high-fructose corn syrup. The results of the present study support previous animal research and both observational and experimental studies in humans indicating that high fructose consumption can lead to NAFLD. The adverse effect is related in part to the excessive energy intake that often accompanies high fructose consumption, but fructose also appears to have a deleterious effect independent of energy intake. Fortunately, the consumption of high-fructose corn syrup in the US appears to have decline over the past several years, presumably because of the well-deserved bad publicity that this sugar has received.

Kavanagh K et al. Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. Am J Clin Nutr. 2013;98:349–357.

Vitamin D for Hepatitis C
Fifty patients with chronic hepatitis C virus (HCV) genotype 2-3 were treated with pegylated interferon-alpha-2a and ribavirin for 24 weeks and were randomly assigned to receive or not to receive 2000 IU per day of vitamin D. Vitamin D supplementation was begun 12 weeks before the start of drug therapy and was continued for the 24 weeks of drug therapy. Twenty-four weeks after treatment was completed, 95% of the patients receiving vitamin D and 77% of those not receiving vitamin D were HCV RNA negative (p < 0.001).
Comment: The results of this study indicate that vitamin D supplementation improved the viral response to pegylated interferon-alpha-2a and ribavirin in patients with chronic HCV genotype 2-3. An earlier study showed a similar beneficial effect of adjunctive vitamin D therapy in patients with HCV genotype 1. The mechanism of action of vitamin D is not clear, although it might be related to a nonspecific improvement of immune function.

Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World J Gastroenterol. 2012;18:800–805.

Green Tea Improves Blood Glucose Control and Insulin Sensitivity
A meta-analysis was conducted on 17 randomized controlled trials, including a total of 1133 subjects (mostly overweight or obese, and/or having type 2 diabetes or borderline diabetes), that examined the effect of green tea on glucose control and insulin sensitivity. Green tea consumption significantly reduced the mean fasting glucose concentrations by 1.6 mg/dl (p < 0.01) and significantly decreased the mean hemoglobin A1c (HbA1c) level by 0.30% (p < 0.01). When only the studies of high methodological quality were included, green tea also significantly reduced fasting insulin concentrations (p = 0.03).
Comment: This meta-analysis found that green tea consumption had a modest beneficial effect on blood glucose control and possibly on insulin sensitivity in overweight/obese individuals and in those with frank or borderline type 2 diabetes. Thus, green tea should be considered as part of a comprehensive program of diet, exercise, and supplementation with blood glucose-regulating nutrients and herbs.

Liu K et al. Effect of green tea on glucose control and insulin sensitivity: a meta-analysis of 17 randomized controlled trials. Am J Clin Nutr. 2013;98:340–348.

Magnesium Prevents Pregnancy-Induced Hypertension
Fifty-nine women (mean age, 29 years) in their first pregnancy were randomly assigned to receive, in double-blind fashion, 300 mg per day of magnesium (as magnesium citrate) or placebo, beginning in week 25 of pregnancy and continuing until delivery. At week 37, the mean diastolic blood pressure was significantly lower in the magnesium group than in the placebo group (72 vs. 77 mm Hg; p = 0.03). At week 37, the proportion of women who had an increase in diastolic blood pressure of at least 15 mm Hg was significantly lower in the magnesium group than in the placebo group (8% vs. 38%; p = 0.01).
Comment: Pregnancy-induced hypertension can have deleterious consequences for both mother and fetus. It is also frequently a harbinger of preeclampsia, which is characterized by hypertension, proteinuria, and edema and associated with increased maternal and fetal morbidity and mortality. Medical treatment options for pregnancy-induced hypertension are limited, since many antihypertensive drugs can harm the fetus. Intravenous administration of large doses of magnesium is a well-recognized treatment for preeclampsia. The results of the present study demonstrate that increasing magnesium intake earlier in pregnancy may help prevent preeclampsia from developing.
Other nutritional interventions that may help prevent pregnancy-induced hypertension and preeclampsia include increasing dietary protein intake and supplementing with vitamin B6 and calcium. Although sodium restriction often lowers blood pressure in people with hypertension, the adverse effects of sodium restriction during pregnancy appear to outweigh any potential benefit.

Bullarbo M et al. Magnesium supplementation to prevent high blood pressure in pregnancy: a randomised placebo control trial. Arch Gynecol Obstet. 2013;288:1269–1274.

'Raft Therapy' for Gastroesophageal Reflux Disease
One hundred ninety-five patients with nonerosive gastroesophageal reflux disease (GERD) were randomly assigned to receive, in double-blind fashion, 20 ml of sodium alginate suspension (20 mg/ml) 3 times per day or 20 mg of omeprazole once a day for 4 weeks. In intent-to-treat analysis, the proportion of patients who reported adequate relief from heartburn or regurgitation was 53.3% with sodium alginate and 50.5% with omeprazole (difference between groups not significant). The incidence of adverse events was around 5% in each group. These results suggest that sodium alginate was as effective as omeprazole for short-term symptomatic relief in patients with nonerosive reflux disease.
Comment: Proton pump inhibitors such as omeprazole are frequently used to treat GERD. By suppressing gastric acid production, these drugs can lead to impaired absorption of calcium, magnesium, iron, vitamin B12, and other nutrients and may also promote small-bowel bacterial overgrowth. Therefore, safer alternatives are needed for patients who require long-term treatment. Sodium alginate is a compound derived from seaweed. It interacts with gastric acid within a few minutes and forms a viscous gel that floats on top of the gastric contents like a raft and physically inhibits the reflux of gastric contents into the esophagus. In a previous study, sodium alginate was more effective than an antacid for providing symptomatic relief in GERD patients. The results of the present study suggest that sodium alginate is at least as effective as omeprazole.

Chiu CT et al. Randomised clinical trial: sodium alginate oral suspension is non-inferior to omeprazole in the treatment of patients with non-erosive gastroesophageal disease. Aliment Pharmacol Ther. 2013;38:1054–1064.

Vitamin D Requirements Differ Between Caucasians and African Americans
Serum levels of 25-hydroxyvitamin D (25[OH]D) and vitamin D-binding protein and bone mineral density (BMD) were measured in 2085 black and white individuals participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort. Participants were also genotyped for 2 common polymorphisms of the vitamin D-binding protein gene (rs7041 and rs4588), the prevalence of which differs between blacks and whites. Mean levels of 25(OH)D (15.6 vs. 25.8 ng/ml; p < 0.001) and vitamin D-binding protein (168 vs. 337 mcg/ml; p < 0.001) were lower in blacks than in whites. Genetic polymorphisms appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D-binding protein and 25(OH)D, respectively. Mean BMD was significantly higher in blacks than in whites (1.05 vs. 0.94 g/cm2; p < 0.001), despite their lower levels of 25(OH)D. Among homozygous participants, blacks and whites had similar levels of bioavailable 25(OH)D.
Comment: Vitamin D-binding protein is the primary vitamin D carrier protein, binding 85% to 90% of circulating 25(OH)D. Vitamin D may be biologically inactive while it is bound to vitamin D-binding protein. In the present study, blacks, as compared with whites, had lower levels of 25(OH)D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25(OH)D. The lower levels of vitamin D-binding protein in blacks appeared to be largely genetically determined.
These findings support the results of other research indicating that the reference range for 25(OH)D should be lower for blacks than for whites. Moreover, an observational study of black women found that those with a serum 25(OH)D level below 20 ng/ml (a level considered to indicate deficiency in whites) had a lower risk of suffering a fracture, when compared with women whose 25(OH)D levels were greater than 20 ng/ml. Thus, giving large doses of vitamin D to blacks for the sole purpose of raising 25(OH)D to a level considered desirable for whites may be inappropriate.

Powe CE et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013;369:1991–2000.

25-Hydroxyvitamin D: Do We Really Know What the Levels Mean?
In 88 patients (median age, 60 years) who presented to the emergency department because of acute hyperglycemia, serum 25-hydroxyvitamin D (25[OH]D) levels were measured on admission and 6 hours after normalization of blood glucose (12–18 hours after admission). The mean serum 25(OH)D level increased from 12.3 ng/ml on admission to 28.2 ng/ml after normalization of blood glucose (p < 0.001). Serum 25(OH)D levels increased in all patients after correction of hyperglycemia.
Comment: These findings suggest that severe hyperglycemia leads to metabolic and endocrine compensations that result in a marked decrease in serum 25(OH)D levels. Correction of hyperglycemia increased 25(OH)D in a matter of hours from levels thought to indicate severe deficiency to levels consistent with normal or near-normal vitamin D status. Because 25(OH) levels increased so rapidly and so dramatically without vitamin D supplementation, it is likely that the low levels associated with hyperglycemia were not indicative of vitamin D deficiency. Other research has shown that 25(OH) is an acute-phase reactant, in that the level declines in response to inflammation. Consequently, in people with acute or chronic inflammatory conditions, a low 25(OH)D level may also not be indicative of vitamin D deficiency.

Numerous observational studies have found that higher serum 25(OH)D levels are associated with better health outcomes. Because of those studies, it has become popular to use relatively large doses of supplemental vitamin D to push serum 25(OH)D to the levels associated with those better health outcomes. However, the association between higher serum 25(OH)D levels and better health might simply indicate that people with good blood glucose control and less inflammation are healthier than people with poor blood glucose control and more inflammation. When the results of ongoing randomized controlled trials are published over the next few years, we will have a better idea about the safety and efficacy of high-dose vitamin D. However, the randomized controlled trials that have been published so far suggest that high doses (such as 6500 IU per day or more) are less effective than moderate doses (such as 800–1200 IU per day) for situations such as osteoporosis prevention and treatment of multiple sclerosis.
To date, I have not found a compelling reason to recommend routine 25(OH)D testing in clinical practice, although I do frequently recommend empirical supplementation with 800 to 2000 IU per day of vitamin D.

Aksu NM et al. 25-OH-Vitamin D and procalcitonin levels after correction of acute hyperglycemia.
Med Sci Monit. 2013;19:264–268.

Alan R. Gaby, MD

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