Literature Review and Commentary

By Alan R. Gaby, MD

Iron Deficiency Anemia and Hemoglobin A1c

In a study of Asian Indians with iron-deficiency anemia (IDA; n = 62) and age- and sex-matched healthy controls without IDA (n = 60), the mean hemoglobin A1c (HbA1c) level was significantly higher in those with IDA than in controls (5.51% vs. 4.85%; p < 0.001). In subjects with IDA, there was a significant negative correlation between the HbA1c concentration and the hemoglobin level, hematocrit, and serum ferritin concentration. In subjects with IDA, the mean HbA1c level fell from 5.51% at baseline to 5.04% after iron supplementation (p < 0.001). Fourteen of 20 subjects (70%) with an HbA1c level in the prediabetes range at baseline had a normal HbA1c level after iron supplementation. Of six patients with a pretreatment HbA1c level in the diabetes range, five reverted to the prediabetes range and one had a normal HbA1c level after iron supplementation.

Comment: One possible interpretation of these findings is that IDA leads to impaired glycemic control and that correction of IDA improves glycemic control. However, that conclusion would contradict previous research indicating that iron deficiency has a positive effect and iron excess has an adverse effect on blood glucose regulation. A more plausible explanation for the findings in this study is that IDA leads to erroneous (i.e., false-high) measurements of HbA1c. In IDA, the quaternary structure of hemoglobin is altered, resulting in increased susceptibility to glycation. In addition, patients with IDA may have a lower proportion of young erythrocytes, because new erythrocytes are not being formed at an adequate rate. The concentration of HbA1c in erythrocytes increases linearly with the cell’s age; therefore, the low proportion of young erythrocytes could result in a higher HbA1c value. After iron supplementation, rapid erythropoiesis results in a lower average erythrocyte age and, consequently, a lower HbA1c level. The results of this study suggest that HbA1c measurements should be interpreted with caution in patients with IDA.

Madhu SV, et al. Effect of iron deficiency anemia and iron supplementation on HbA1c levels – Implications for diagnosis of prediabetes and diabetes mellitus in Asian Indians. Clin Chim Acta. 2017;468:225-229.

Blue Light-Blocking Lenses to Treat Insomnia

Fourteen individuals (aged 18-65 years; mean age, 46.6 years) with insomnia were randomly assigned to wear blue light-blocking amber lenses or clear placebo lenses for two hours before bedtime for seven days. After a four-week washout period, each person wore the alternate lenses for an additional seven days. The blue light-blocking lenses blocked about 65% of the blue light, whereas the clear lenses blocked about 10% of the blue light. Compared with the clear lenses, the blue light-blocking lenses significantly improved the mean Pittsburgh Insomnia Rating Scale score by 18.3% (p = 0.023), significantly increased mean total sleep time (399 vs. 347 minutes; p < 0.01), and significantly improved sleep quality (p < 0.04) and sleep soundness (p = 0.004).

Comment: Exposure in the evening or at night to normal room lighting or to light-emitting diode (LED) computer screens reduces melatonin secretion and also increases arousal independently of melatonin secretion. Each of these effects can interfere with normal sleep patterns. The blue-light portion of the visible spectrum (450-480 nm) appears to be the most efficient wavelength range for suppressing melatonin secretion and increasing arousal. Most computers, televisions, and smart phones, and many light bulbs are lit by LEDs, which have a peak wavelength of around 460 nm. As many as 90% of Americans use some type of LED device within an hour of bedtime. The results of the present study suggest that wearing blue light-blocking lenses for two hours before bedtime can improve sleep in people with insomnia.

Shechter A, et al. Blocking nocturnal blue light for insomnia: a randomized controlled trial. J Psychiatr Res. 2018;96:196-202.

Cherry Juice for Insomnia

Eleven healthy subjects (mean age, 68 years) with insomnia were randomly assigned to receive, in double-blind fashion, 240 ml of tart cherry juice or placebo twice a day, in the morning and one hour before bedtime, for 14 days. After a two-week washout period, each person received the alternate treatment for an additional 14 days. The placebo contained fructose, glucose, and lemon powder, and looked and tasted like cherry juice. An overnight polysomnographic sleep study was conducted at the end of each treatment period. Three subjects were found on polysomnography to have sleep apnea and were excluded from the analysis. Among the remaining eight subjects, mean total sleep time according to polysomnography was 84 minutes longer with cherry juice than with placebo (p < 0.02). Sleep efficiency as determined by questionnaire was significantly better with cherry juice than with placebo (p = 0.03), but sleep efficiency as determined by polysomnography was only nonsignificantly better with cherry juice than placebo (p = 0.19). The mean serum kynurenine-to-tryptophan ratio was significantly lower with cherry juice than with placebo (p < 0.05), indicating less metabolism of tryptophan to kynurenine.

Comment: Tryptophan is metabolized to serotonin and melatonin, both of which play a role in sleep. Tryptophan is also metabolized by a separate pathway to kynurenine by the enzyme, indoleamine 2,3-dioxygenase (IDO). This enzyme is inhibited by inflammation, and cherry juice has been reported to have an anti-inflammatory effect. In vitro, procyanidin B-2 (a flavonoid present in cherries and apples) inhibited IDO in a dose-dependent manner. Inhibiting the metabolism of tryptophan to kynurenine would make more tryptophan available to be converted to serotonin and melatonin.

The results of the present study suggest that consumption of cherry juice can increase sleep time and improve sleep efficiency in elderly people with insomnia, possibly by increasing the availability of tryptophan for serotonin and melatonin synthesis. However, a larger study is needed to confirm these findings. Of note, only one of the seven variables assessed on the questionnaire (i.e., sleep efficiency) showed a statistically significant advantage of cherry juice over placebo. The fact that no adjustment was made for multiple comparisons increases the probability that the significant improvement in sleep efficiency was due to chance.

Losso JN, et al. Pilot study of the tart cherry juice for the treatment of insomnia and investigation of mechanisms. Am J Ther. 2018;25:e194-e201.

Do Cooking Methods Affect Diabetes Risk?

A prospective study was conducted among 52,752 women from the Nurses’ Health Study (NHS) (followed from 1996 to 2012), 60,809 women from NHS II (followed from 2001 to 2013), and 24,679 men from the Health Professionals Follow-Up Study (followed from 1996 to 2012) who were free of diabetes, cardiovascular disease, and cancer at baseline. During 1.74 million person-years of follow-up, 7,895 new cases of type 2 diabetes were documented. After adjustment for baseline body mass index and total consumption of red meat, chicken, and fish, higher frequency of open-flame and/or high-temperature cooking was independently associated with an increased risk of type 2 diabetes. When comparing open-flame and/or high-temperature cooking more than 15 times per month with less than four times per month, the pooled hazard ratio for type 2 diabetes was 1.28 (i.e., a 28% increase in risk; p for trend < 0.001). The association remained significant when red meat and chicken were examined separately.

Comment: In this study, open-flame and/or high-temperature cooking of red meat and chicken was associated with an increased risk of developing type 2 diabetes, independently of the amounts of these foods consumed. High-temperature cooking of meats and of various other foods results in the formation of advanced glycation end products (AGEs). AGEs have been reported to promote insulin resistance and to damage pancreatic islet cells in mice¹ and to accelerate the progression of nephropathy in mouse models of type 1 and type 2 diabetes.² Consumption of a high-AGE diet has also been shown to promote insulin resistance in humans with type 2 diabetes³ and in overweight nondiabetic individuals.⁴

The AGE content of the diet can be decreased by cooking at lower temperatures and in the presence of water or other liquids. Thus, boiling, steaming, or poaching of foods results in less AGE formation than does grilling, frying, roasting, or baking. Of course, raw foods have a very low AGE content.

Liu G, et al. Meat cooking methods and risk of type 2 diabetes: results from three prospective cohort studies. Diabetes Care. 2018;41:1049-1060.

How Much Vitamin D for Infants?

Nine hundred seventy-five healthy term infants in Finland (all of Northern European ethnicity) were randomly assigned to receive 400 or 1,200 IU per day of vitamin D from age two weeks to 24 months. The primary outcome measures were bone strength of the left tibia (as determined by bone mineral content, bone mineral density, cross-sectional area, and polar moment of inertia [an indicator of resistance to torsion]) and incidence of parent-reported infections at 24 months. There was no significant difference between groups with respect to any of the four measures of bone strength or in the incidence of infections.

Comment: Guidelines for vitamin D supplementation for children are mostly based on studies focusing on prevention of rickets. The optimal dose for bone strength and infection prevention in healthy infants remains unclear. In this study of Northern European infants, 400 IU per day of vitamin D appeared to be adequate for children younger than 2 years of age, and increasing the dose to 1,200 IU per day had no effect on bone strength or incidence of infections. An earlier double-blind study of healthy, term breastfed infants in Montreal, Canada, found that gross motor development was significantly better in those receiving 400 IU per day of vitamin D than in those receiving 800 or 1,200 IU per day.⁵ Thus, the available data suggest that healthy infants should not be given more than 400 IU per day of vitamin D unless there is evidence that the benefits of using a higher dose would outweigh the risks for a particular child.

Rosendahl J, et al. Effect of higher vs standard dosage of vitamin D₃ supplementation on bone strength and infection in healthy infants: a randomized clinical trial. JAMA Pediatr. 2018;172:646-654.

High-Dose Vitamin D May Adversely Affect Muscle Strength and Physical Performance

Eighty-one postmenopausal Danish women (aged 60-80 years) with a serum 25-hydroxyvitamin D level below 20 ng/ml (mean, 13.2 ng/ml) and secondary hyperparathyroidism were randomly assigned to receive, in double-blind fashion, 2,800 IU per day of vitamin D3 or placebo for three months during the winter. Vitamin D supplementation increased the mean 25-hydroxyvitamin D level by 230% and decreased the mean parathyroid hormone level by 17% (p < 0.001). Compared with placebo, vitamin D reduced maximal handgrip strength by 9% (p < 0.01) and knee flexion strength by 13% (p = 0.02), and increased the time required to complete the Timed Up and Go test by 4.4%; (p < 0.05). Levels of physical activity, postural stability, well-being, and quality of life did not change.

Comment: Vitamin D deficiency has been associated with reduced muscle strength, physical performance, postural stability, well-being, and quality of life. When vitamin D deficiency is the cause of or contributes to impaired physical functioning, vitamin D supplementation would be expected to lead to improvement. However, a growing number of studies in people with various clinical conditions suggest that high doses of vitamin D are not more effective, and may even be less effective, than moderate doses of the vitamin (such as 800-1,200 IU per day). In the present study, supplementation with 2,800 IU per day of vitamin D for three months had an adverse effect on certain parameters of physical performance in postmenopausal women with low baseline levels of 25-hydroxyvitamin D.

Studies on vitamin D supplementation to prevent falls in elderly people have produced conflicting results. However, the trend in those studies appeared to suggest that moderate doses prevent falls, higher doses are less effective, and periodic administration of large bolus doses actually increases the risk of falls.

Short-term administration of large doses of vitamin D may be appropriate for correcting a deficiency. However, the present study, when combined with other research, suggests that large doses should not, in most cases, be given for long periods of time. As I have pointed out elsewhere, serum 25-hydroxyvitamin D appears to be an unreliable indicator of vitamin D status.⁶ A case can be made that practitioners should not use that test as a guide for vitamin D dosing. At present there is no convincing evidence that routinely basing dosage recommendations on 25-hydroxyvitamin D levels is safe or improves outcomes. For adult patients who are likely to benefit from vitamin D supplementation, my usual practice has been to recommend 800-1,200 IU per day and not to measure the 25-hydroxyvitamin D level. The final word on proper vitamin D dosing is not yet in.

Bislev LS, et al. Effects of vitamin D3 supplementation on muscle strength, mass, and physical performance in women with vitamin D insufficiency: a randomized placebo-controlled trial. Calcif Tissue Int. 2018 Jun 21 [Epub ahead of print].

Pancreatic Enzyme Therapy for Pancreatic Cancer

Eighty-eight patients with inoperable pancreatic cancer were randomly assigned to receive, in open-label fashion, pancreatic enzymes (pancrelipase; 48,000 lipase units per meal) or no pancreatic enzymes (control group). Ninety percent of the patients had exocrine pancreatic insufficiency at baseline, as determined by the N-benzoyl-tyrosyl para-aminobenzoic acid (NBT-PABA) test. The primary outcome measure was the change in body mass index at eight weeks. Secondary outcomes included other measures of nutritional status, such as hemoglobin, albumin, total cholesterol, and triglycerides. There was no significant effect of pancreatic enzymes on any of the outcome measures. Median survival time was higher in the group receiving pancreatic enzymes than in the control group (19 vs 12 months; p = 0.07).

Comment: Pancreatic cancer is frequently associated with exocrine pancreatic insufficiency, which may lead to decreased nutritional status. However, the role of pancreatic enzyme replacement therapy has not been well studied. In the present trial, administration of pancreatic enzymes did not improve nutritional status in patients with inoperable pancreatic cancer. However, it did increase median survival time by seven months, an effect that was of borderline statistical significance.

In 1999, Gonzalez and Isaacs reported the results of 11 patients with pancreatic cancer who were treated with a program that included large doses of pancreatic enzymes, dietary modifications, and coffee enemas. Median survival time in those patients was 17 months, which was substantially higher than the median survival time of six months that was reported in the then-current literature for similar patients.⁷

Both of these studies suggest that pancreatic enzyme supplementation can prolong survival in patients with pancreatic cancer, even if it does not improve nutritional status.

Saito T, et al. A multicenter open-label randomized controlled trial of pancreatic enzyme replacement therapy in unresectable pancreatic cancer. Pancreas. 2018;47:800-806.

Thyroid Hormone Improves Fatty Liver

Twenty men (mean age, 48 years; mean body mass index, 30.9 kg/m²) with type 2 diabetes and nonalcoholic fatty liver disease, who were considered euthyroid by laboratory criteria (a normal free-T4 level and a TSH level between 1 and 10 mIU/L) were treated with levothyroxine, with the dose titrated to maintain a low-normal TSH level (0.34-1.70 mIU/L). The treatment was continued for 16 weeks after the maintenance dose was achieved. Patients were advised to maintain their usual diet and exercise patterns. At baseline, the mean TSH level was 1.86 mIU/L, which decreased to a mean of 1.41 mIU/L during the titration phase. The median maintenance dose of levothyroxine was 18.75 µg per day (range, 12.5 µg every 2 days to 87.5 µg per day). Compared with baseline, the mean fat content of the liver decreased by 12% (p < 0.05). Mean body weight decreased by 1 kg during the study (p < 0.05).

Comment: These results suggest that low-dose levothyroxine can decrease intrahepatic lipid content in patients with type 2 diabetes and nonalcoholic fatty liver disease. The mechanism of action of thyroid hormone is not clear. It is unlikely that the beneficial effect was due to the small amount of weight the patients lost during the study.

Bruinstroop E, et al. Low-dose levothyroxine reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and NAFLD. J Clin Endocrinol Metab. 2018;103:2698-2706.