Alan R. Gaby, MD

delta-Tocotrienol for Nonalcoholic Fatty Liver Disease

Seventy-one adults (mean age, 44.4 years; mean body mass index, 31.2 kg/m2) with nonalcoholic fatty liver disease were studied. All patients had ultrasound-proven hepatic steatosis and mild-to-moderate elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (not more than 4 times the upper limit of normal). The patients were randomly assigned to receive, in double-blind fashion, 300 mg of delta-tocotrienol twice a day or placebo for 24 weeks. The proportion of patients who showed a decrease in the severity of hepatic steatosis was significantly greater in the delta-tocotrienol group than in the placebo group (31.4% vs. 12.5%; p < 0.05). Compared with placebo, delta-tocotrienol significantly decreased mean values for ALT and AST, significantly decreased insulin resistance, and significantly decreased the mean concentration of C-reactive protein. The mean decrease in body mass index was significantly greater in the delta-tocotrienol group than in the placebo group (-2.38 vs. -0.73 kg/m2; p < 0.001). No adverse events were reported.

Comment: “Vitamin E” is a collective term for eight naturally occurring compounds: four tocopherols (alpha-, beta-, gamma-, and delta-) and four tocotrienols (alpha-, beta-, gamma-, and delta-). Tocotrienols are found in relatively high concentrations in grains (e.g., oats, barley, and rye) and in certain vegetable oils (e.g., palm oil and rice bran oil). Studies in rats and mice found that tocotrienols, especially delta-tocotrienol, have antioxidant and anti-inflammatory effects, improve insulin resistance, and decrease hepatic steatosis. In the present study, administration of delta-tocotrienol improved biochemical markers of hepatocellular injury and steatosis, and decreased insulin resistance and inflammation, in patients with nonalcoholic fatty liver disease. delta-Tocotrienol is commercially available as an individual supplement (90% delta- and 10% gamma-tocotrienol).

Pervez MA, et al. Delta-tocotrienol supplementation improves biochemical markers of hepatocellular injury and steatosis in patients with nonalcoholic fatty liver disease: A randomized, placebo-controlled trial. Complement Ther Med. 2020;52:102494.

Vitamin E for Nonalcoholic Steatohepatitis in HIV-Infected Patients

Twenty-seven HIV-infected patients with nonalcoholic steatohepatitis received 800 IU per day of vitamin E (alpha-tocopherol) for 24 weeks. Compared with baseline, a significant decrease was seen in the median alanine aminotransferase level (from 50 IU/L to 23 IU/L) and in the median degree of hepatic steatosis. There was no significant change in body mass index.

Comment: Nonalcoholic fatty liver disease can manifest either as fatty liver alone (hepatic steatosis) or as a combination of fatty liver and hepatic injury (hepatitis). In the latter case it is referred to as nonalcoholic steatohepatitis. Several studies have demonstrated that alpha-tocopherol is beneficial for patients with nonalcoholic fatty liver disease who are not infected with HIV. The present study found that alpha-tocopherol is also useful for patients with HIV. Based on this research and the study on tocotrienols described above, it is possible that combining tocopherols and tocotrienols would be more effective than either treatment alone for patients with nonalcoholic fatty liver disease.

Sebastiani G, et al. Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients. AIDS. 2020;34:237-244.

Tocotrienols for Diabetic Kidney Disease

Fifty-nine Malaysian patients (median age, 67 years) with diabetic kidney disease (mostly stage 3A) were randomly assigned to receive, in double-blind fashion, 200 mg of tocotrienol-rich vitamin E (Tocovid SupraBio; Hovid Berhad, Ipoh, Malaysia) twice a day or a placebo for 12 months. The mean serum creatinine concentration at baseline was 1.38 mg/dl in the tocotrienols group and 1.33 mg/dl in the placebo group. Serum creatinine was measured every two months for 12 months. In the tocotrienols group, the mean creatinine level was lower than the baseline value at all time points, whereas in the placebo group the mean level was higher than the baseline value at all time points. The difference in the change between groups was significant after 4, 6, and 8 months, but not after 10 or 12 months. For estimated glomerular filtration rate (eGFR), in the tocotrienols group the mean value was higher than at baseline at all time points, whereas in the placebo group the mean value was lower than baseline at all time points. The difference in the change between groups was significant after 4, 6, 8, 10, and 12 months. Among patients with stage 3 chronic kidney disease (eGFR of 30-60 ml/min/1.73 m2), at 12 months the difference in the change in eGFR between groups was 6.28 ml/min/1.73 m2 (p = 0.022).

Comment: This study demonstrated that supplementation with tocotrienol-rich vitamin E prevented the decline in kidney function in patients with diabetic nephropathy. The mechanism of action is not clear.

Koay YY, et al. A phase IIb randomized controlled trial investigating the effects of tocotrienol-rich vitamin E on diabetic kidney disease. Nutrients. 2121;13:258.

Selenium, Coenzyme Q10, and Renal Function

Four hundred forty-three community-dwelling elderly Swedish individuals (aged 70-88 years) were randomly assigned to receive, in double-blind fashion, coenzyme Q10 (CoQ10; 100 mg twice a day) and selenium (200 µg per day from selenium yeast) or placebo for four years. The present study was a subgroup of analysis of the 215 individuals who agreed to provide blood samples during the entire intervention period and who also survived for the entire intervention period. At baseline, the mean serum selenium level was 67 µg/dl, which was below the “adequate” concentration of 100 µg/L. In the selenium/CoQ10 group, the mean serum creatinine concentration decreased from 1.04 mg/dl at baseline to 0.87 mg/dl after four years. The mean creatinine level did not change in the placebo group; and at the end of the treatment period, the level was significantly lower in the selenium/CoQ10 group than in the placebo group (0.87 vs. 1.03 mg/dl; p = 0.0002).

Comment: In this study, long-term supplementation with a combination of selenium and CoQ10 appeared to improve or slow the decline in renal function in elderly Swedish individuals. Low selenium intake is common in European countries, and serum selenium measurements at baseline suggested that mild selenium deficiency was common in this population. It is not clear whether the findings from this study would apply to regions where selenium status is adequate. It is also not known whether the beneficial effect on kidney function was due mainly to selenium, CoQ10, or their combination. Age-related decline in renal function is very common, so the possibility that this decline can be prevented warrants further study.

Alehagen U, et al. Selenium and coenzyme Q10 supplementation improves renal function in elderly deficient in selenium: observational results and results from a subgroup analysis of a prospective randomised double-blind placebo-controlled trial. Nutrients. 2020;12:E3780.

Vitamin D Toxicity Persists for a Long Time

A 25-year-old male presented with hypercalcemia and acute kidney injury due to vitamin D toxicity. He had consumed 50,000 IU per day of vitamin D for around seven months, with the last dose taken two weeks prior to presentation. His serum 25-hydroxyvitamin D (25[OH]D) level was reported as greater than 126 ng/ml (more precise quantification was done). Twenty-nine days after his last vitamin D dose the 25(OH)D level was 492 ng/ml, and 81 days after the last dose the level was 274 ng/ml.

Comment: This case report demonstrates that serum 25(OH)D levels can remain markedly elevated for months after high-dose vitamin D is discontinued. Because it is fat-soluble, vitamin D can accumulate in adipose tissue, and this accumulation may not necessarily be accompanied by a substantial increase in the serum 25(OH)D level. In one study, 29 subjects were randomly assigned to receive 20,000 IU of vitamin D3 or placebo once a week for three to five years. At the end of the treatment period, the mean concentration of vitamin D in adipose tissue had increased by 550%, whereas the serum 25(OH)D level had increased by only about 60%. Therefore, in people taking large doses of vitamin D, a normal 25(OH)D level may not rule out the possibility of impending and persistent vitamin D toxicity.

Houghton CC, Lew SQ. Long-term hypervitaminosis D-induced hypercalcaemia treated with glucocorticoids and bisphosphonates. BMJ Case Rep. 2020;13:e233853.

Ivermectin for COVID-19

A chart review was conducted on 280 patients hospitalized with COVID-19 between March 15 and May 11, 2020, at four hospitals in Florida. Sixty-two percent of the patients received ivermectin at the discretion of the attending physician. Most patients, regardless of whether they were given ivermectin, received hydroxychloroquine, azithromycin, or both. The mortality rate was 15.0% in patients who received ivermectin and 25.2% in those who did not receive the drug (p = 0.03). Among patients with severe pulmonary involvement, mortality was markedly lower in those who received ivermectin than in those who did not (38.8% vs. 80.7%; p = 0.001). After adjustment for potential confounding variables and mortality risk, treatment with ivermectin was associated with a 73% reduction in mortality (p = 0.03).

Comment: Ivermectin, which was developed in the 1970s, is considered a safe and effective treatment for certain parasitic infections. Over the past 30 years, about 3.7 billion doses have been administered worldwide. Ivermectin has also demonstrated activity in vitro against a broad range of viruses, including HIV, influenza, and Zika virus. Recently, it was found to be a potent in vitro inhibitor of the COVID-19 virus, producing a 99.8% reduction in viral RNA after 48 hours. Some doctors are using ivermectin to treat COVID-19 patients, but no randomized controlled trials have been completed at the time of this writing. The results of this observational study raise the possibility that ivermectin can substantially decrease mortality in patients with COVID-19.

Rajter JC, et al. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: The Ivermectin in COVID Nineteen Study. Chest. 2021;159:85-92.

Aloe vera for Atrophic Vaginitis, or More Iranian Research Fraud?

Sixty-six postmenopausal Iranian women with symptoms of atrophic vaginitis were randomly assigned to receive, in double-blind fashion, an intravaginal cream containing conjugated estrogens or Aloe vera. The treatment was administered nightly for two weeks, followed by three nights a week for another four weeks. Significant improvements in histologic findings and symptoms were seen in both groups, and there was no significant difference efficacy between groups.

Comment: I have noted in previous issues of the Townsend Letter that a large proportion of the research on natural medicine coming from Iran appears to be fraudulent. Several points in the present study raise concerns:

1. Unusually rapid recruitment: During a 21-day period, 220 women were assessed for eligibility, and 66 were enrolled in the study. There was no mention of how many clinics were involved in recruiting patients. Based on the affiliations listed for the authors, it appears that there was a maximum of two clinics involved. Even with two clinics, it would be unusual for so many patients with atrophic vaginitis to have been evaluated and enrolled in such a short period of time.
2. Discrepancy regarding sample size: The paper stated that the sample size was 66 patients, whereas the registration document in the Iranian Registry of Clinical Trials (IRCT) stated that the target sample size was 50. Since the IRCT document was registered after the study was completed, it is difficult to reconcile this discrepancy.
3. Discrepancy regarding the treatment regimen: The paper stated that the two treatments were administered every night for two weeks, then three times a week for four weeks. The IRCT document stated that the treatments were administered every night for 10 days, then three times a week until six weeks. The paper also stated that each dose of each vaginal cream was 5 mg. This clearly appears to be a misprint, since 5 mg is a miniscule dose of cream, which would be very difficult to measure and administer. The fact that this apparent misprint was not caught by the reviewers speaks to the laxity of the peer review process.
4. Contradictory outcome measure: Satisfaction with the treatment was measured on a 5-point scale (very satisfied, satisfied, uncertain, dissatisfied, and very dissatisfied). It was not stated whether the higher numbers referred to better or worse outcomes. The paper stated that all patients in both groups were satisfied or very satisfied with their treatment. However, the mean score was 3.0 in one treatment group and 3.4 in the other treatment group (it was not clear which group had which score). A score of 3.0 corresponds to “uncertain” on the 5-point scale. It is therefore impossible for all patients in both groups to have been satisfied or very satisfied.
5. Funding issue: Double-blind studies are expensive, so it is difficult to believe that the funding source would have provided money for a randomized controlled trial when there had been no prior evidence from case reports or uncontrolled trials that Aloe vera vaginal cream is effective for atrophic vaginitis.
6. Implausible results: Call me overly skeptical if you wish, but I find it hard to believe that a cream containing 2% Aloe vera could be as effective as estrogen cream for improving symptoms and reversing histologic abnormalities.

Poordast T, et al. Aloe vera; a new treatment for atrophic vaginitis, a randomized double-blinded controlled trial. J Ethnopharmacol. 2021;24:113760.

Can N-Acetylcysteine Prevent Acetaminophen Hepatotoxicity?

Twenty-four healthy volunteers (mean age, 27.4 years) were given 1 g of acetaminophen four times a day for four days. During that time, they were randomly assigned to receive, in double-blind fashion, 300 mg of N-acetylcysteine (NAC) twice a day or placebo. On the fourth day, each person underwent a thermal pain test and then received 2 g of acetaminophen plus 600 mg of NAC or placebo (depending on their treatment assignment). The thermal pain test was then repeated after 1, 2, 3, and 4 hours. Two weeks later, the procedures were repeated, but each subject received the alternate treatment (NAC or placebo). The primary outcome measure was the pain-relieving effect of acetaminophen, as determined by the area under the curve (0-240 minutes) of pain intensity after thermal pain stimulation. Treatment with NAC did not decrease the pain-relieving effect of acetaminophen. After four days of treatment with 4 g per day of acetaminophen, the mean whole-blood concentration of glutathione was similar to its baseline value in the NAC group, but fell significantly in the placebo group (p < 0.03 for the difference in the change between groups).

Comment: Acetaminophen toxicity is the leading cause of hospital admission for acute liver failure in the United States, accounting for 56,000 emergency room visits per year. Acetaminophen depletes hepatic glutathione, and this depletion plays a role in the pathogenesis of the liver damage. NAC stimulates the production of glutathione, and intravenous NAC is the treatment of choice for acetaminophen toxicity. In the present study, oral administration of NAC decreased the acetaminophen-induced decline in whole-blood glutathione levels without compromising the pain-relieving effect of the drug. This finding raises the possibility that co-administration of NAC can decrease the risk of developing liver damage from acetaminophen.

Pickering G, et al. N-acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double-blind controlled trial in healthy subjects. Fundam Clin Pharmacol. 2019;33:303-311.

References
1. Didriksen A, et al. Vitamin D3 increases in abdominal subcutaneous fat tissue after supplementation with vitamin D3. Eur J Endocrinol. 2015;172:235-241.

This column was originally published in Townsend Letter (June 2021).

Published April 20, 2024

About the Author

Alan R. Gaby, MD, 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.