Vitamin D for Palliative Care in Cancer Patients

Two hundred forty-four Swedish patients with advanced cancer and a serum 25-hydroxyvitamin D level below 20 ng/ml (median, 15.2 ng/ml) who were receiving home-based palliative care were randomly assigned to receive, in double-blind fashion, 4,000 IU per day of vitamin D or placebo for 12 weeks. One hundred fifty patients completed the trial. Most of the dropouts were due to death from cancer. Among patients who completed the trial, the increase in opioid use was significantly smaller in the vitamin D group than in the placebo group (p = 0.03). In addition, the mean severity of fatigue was significantly less in the vitamin D group than in the placebo group (p < 0.01).

Comment: Vitamin D deficiency is common in patients with advanced cancer. Likely contributing factors include poor appetite, decreased capacity to absorb dietary vitamin D, and lack of sunlight exposure. The results of the present study indicate that correction of vitamin D deficiency may improve fatigue and decrease the need for opioids in patients with advanced cancer who are receiving palliative care.

I once consulted with the wife of a patient who was receiving home hospice care for advanced cancer. Because of severe fatigue, he was in bed most of the time. He had not been out of the house for many months, and his diet contained little vitamin D. I recommended that he take 10,000 IU of vitamin D per day for one week, and then a lower dose for maintenance. Within 24 hours of taking the first dose, he was feeling so much better that he got up, got dressed, and took his wife out to dinner. Although he succumbed to his illness, vitamin D supplementation improved the quality of the final weeks of his life.

Helde Frankling M, et al. ‘Palliative-D’ – Vitamin D supplementation to palliative cancer patients: a double blind, randomized placebo-controlled multicenter trial. Cancers. 2021;13:3707.

CBD Oil As a Potential Treatment for Lung Cancer

A woman in her eighties was diagnosed in June 2018 by CT scan and lung biopsy with non-small cell lung carcinoma in the right middle lobe. She declined conventional therapy and chose to self-administer cannabidiol (CBD) oil at a dose of 0.5 ml, usually three times per day, occasionally twice a day. Serial imaging showed that her cancer decreased in size progressively from 41 mm to 10 mm over a period of 2.5 years.

Comment: Cannabinoids, which are chemically similar to our own body’s endocannabinoids, can interact with signaling pathways to control the fate of cells, including cancer cells. Previous studies on the use of cannabinoids as a treatment for cancer have produced conflicting results. Based on the encouraging results in this case report, further studies on the use of CBD oil seem warranted.

Liew KL, et al. Lung cancer patient who had declined conventional cancer treatment: could the self-administration of ‘CBD oil’ be contributing to the observed tumour regression? BMJ Case Rep. 2021;14:e244195.

Vitamin C Improves Mental Vitality

In a cross-sectional study of 214 healthy young Korean adults (aged 20-39 years), there was a positive association between the serum vitamin C concentration and the ability to maintain attention (p = 0.02). Fifty-five percent of participants had an “inadequate” serum vitamin C level, which was defined as below 0.88 mg/dl. For comparison, the usual laboratory reference range for vitamin C is 0.6-2.0 mg/dl. Fifty individuals with “inadequate” vitamin C levels were randomly assigned to receive, in double-blind fashion, 500 mg of vitamin C twice a day or placebo for four weeks. Compared with placebo, vitamin C significantly increased attention (p = 0.03), engagement in work (p = 0.03), and cognitive function (as assessed by the Stroop color-word test; p = 0.04), and nonsignificantly improved fatigue (p = 0.06).

Comment: This study found that suboptimal vitamin C status is common among healthy young Korean adults, and that improving vitamin C status can improve work motivation, attention, and performance on cognitive tasks that require sustained attention. In a study of US adults (aged 20-59 years) participating in one of the National Health and Nutrition Examination Surveys, mean vitamin C intake was 85 mg per day among men and 67 mg per day among women.¹ The Recommended Dietary Allowance (RDA) for vitamin C is 90 mg per day for men and 75 mg per day for women. Thus, more than half of the adults in this study were consuming less than the RDA for vitamin C. Those individuals might experience benefits similar to those reported in the present study if they increased their vitamin C intake.

Sim M, et al. Vitamin C supplementation promotes mental vitality in healthy young adults: results from a cross-sectional analysis and a randomized, double-blind, placebo-controlled trial. Eur J Nutr. 2022;61:447-459.

Vitamin D Supplementation During Pregnancy Improves Children’s Tooth Development

Six hundred twenty-three pregnant women participating in the Copenhagen Prospective Studies on Asthma in Childhood were randomly assigned to receive, in double-blind fashion, high-dose vitamin D (2,800 IU per day) or standard-dose vitamin D (400 IU per day), beginning at 24 weeks of gestation and continuing until one week postpartum. The mean serum 25-hydroxyvitamin D level at baseline was 30.7 ng/ml, which suggests that most of the women had adequate vitamin D status. A dental examination was performed at age 6 years in 496 children of the women in the study. An enamel defect was defined as having at least one molar affected by an opacity, enamel breakdown, and/or atypical restoration. The incidence of enamel defects in the permanent teeth was lower with high-dose vitamin D than with the standard dose (15.1% vs. 27.5%; odds ratio = 0.47; 95% confidence interval [CI], 0.27-0.81). Similar results were seen in the primary (baby) teeth (8.6% vs. 15.9%; odds ratio = 0.50; 95% CI, 0.28-0.87).

Comment: Defective enamel development affects up to 38% of schoolchildren. Impaired enamel formation can result in pain and rapid caries progression. Vitamin D plays a role in enamel development. In the present study, 2,800 IU per day of supplemental vitamin D was more effective than 400 IU per day for promoting satisfactory tooth development in the offspring of Danish women. This study was a post-hoc analysis of a previous study that found that the higher dose of vitamin D decreased the incidence of troublesome lung symptoms in this same group of children.²

Denmark is much farther north of the Equator than the northernmost parts of the United States. Therefore, Danish individuals receive less sunlight than those living in the US. Additional research is needed to determine whether the findings from this study apply to people living in the US.

Norrisgaard PE, et al. Association of high-dose vitamin D supplementation during pregnancy with the risk of enamel defects in offspring: a 6-year follow-up of a randomized clinical trial. JAMA Pediatr. 2019;173:924-930.

Omega-3 Fatty Acids and Heart Failure

In the Vitamin D and Omega 3 Trial (VITAL), 25,871 US adults (mean age, 67.1 years) were randomly assigned to receive, in double-blind fashion, 2,000 IU per day of vitamin D, 1,000 mg per day of omega-3 fatty acids, both treatments, or placebo for a median duration of 5.3 years. The present study, an ancillary study of VITAL, examined the effect of omega-3 fatty acids on the risk of hospitalization for heart failure (HF). The effect of omega-3 fatty acids was found to depend on whether the participants had type 2 diabetes. When omega-3 supplements were compared with placebo, the hazard ratio (HR) for first HF hospitalization was 0.69 (95% confidence interval [CI], 0.50-0.95) in participants with type 2 diabetes and 1.09 (95% CI, 0.88-1.34) in those without type 2 diabetes (p for interaction < 0.02). The presence of type 2 diabetes also modified the effect of omega-3 fatty acids on the risk of recurrent HF hospitalization (HR = 0.53; 95% CI, 0.41-0.69 in participants with type 2 diabetes; HR = 1.07; 95% CI, 0.89-1.28 in those without type 2 diabetes; p for interaction < 0.0001). In a secondary analysis, omega-3 supplementation reduced recurrent HF hospitalization (but not initial HF hospitalization) only in Black participants (p for interaction < 0.05).

Comment: While some previous studies found that omega-3 fatty acid supplementation prevented the development of HF, other studies found no beneficial effect. The results of the present study suggest that the effect of omega-3 fatty acids on risk of HF differs in different subsets of the population. Specifically, omega-3 fatty acids may help prevent HF in people with type 2 diabetes and in Black individuals, but not in others.

The literature on omega-3 fatty acids for the prevention and treatment of cardiovascular disease is voluminous, complex, contradictory, and confusing. Presumably, individuals with lower baseline omega-3 fatty acid intake, a higher level of systemic inflammation, or a hypercoagulable state would be more likely than others to benefit from omega-3 fatty acid supplementation. The present study suggests that Blacks and people with type 2 diabetes are also likely to benefit from omega-3 fatty acids.

Djousse L, et al. Diabetes mellitus, race, and effects of omega-3 fatty acids on incidence of heart failure hospitalization. JACC Heart Fail. 2022;10:227-234.

Interpreting 25-Hydroxyvitamin D Levels

The authors of this letter to the editor point out that there has been considerable controversy about how to interpret serum 25-hydroxyvitamin D (25[OH]D) levels. Because 25(OH)D is an acute phase reactant, the level declines in response to inflammation. Consequently, a low 25(OH)D level may not necessarily indicate vitamin D deficiency. The innate immune system responds to metabolic stress with chronic low-grade inflammation, as manifested by a small increase in the C-reactive protein (CRP) level. Minor CRP elevations are associated with many medical conditions and with various unhealthy lifestyles that lead to metabolic stress. Examples include diabetes, obesity, hypertension, atrial fibrillation, obstructive sleep apnea, excessive nutrient consumption, poor sleep, and unhealthy diets.

Low 25(OH)D levels are associated with numerous medical conditions that have an inflammatory component, including preeclampsia, autoimmune disorders, infectious diseases, cardiovascular disease, cancer, type 2 diabetes, subcutaneous and visceral adiposity and obesity, neurological disorders, and acute pancreatitis. These associations have generally been interpreted to indicate that vitamin D deficiency predisposes to or aggravates those conditions, rather than considering the possibility that the conditions themselves lead to a low 25(OH)D level. About 30% of the general population has a minor CRP elevation, a fact that might explain why low 25(OH)D levels are so common. The authors concluded that 25(OH)D levels are unlikely to be a reliable measure of vitamin D status in people with one of the many conditions that are associated with systemic inflammation. Interpretation of a low 25(OH)D level may be aided by measuring the CRP level.

Comment: I have been making these same arguments about vitamin D testing for at least 15 years. It is encouraging to see that two other doctors have come to the same conclusion. Perhaps I was ahead of my time, or perhaps there are now two more doctors who don’t know what they are talking about. I vote for the former.

Antonelli M, Kushner I. Low serum levels of 25-hydroxyvitamin D accompany severe COVID-19 because it is a negative acute phase reactant. Am J Med Sci. 2021;36:333-335.

Ginger for Symptoms of Hypothyroidism, or More Iranian Research Fraud?

Sixty hypothyroid Iranian patients with persistent hypothyroid symptoms despite having a normal TSH level while on levothyroxine therapy were randomly assigned to receive, in double-blind fashion, 500 mg of ginger powder twice a day or placebo for 30 days. Compared with placebo, ginger significantly improved hypothyroid symptoms, as assessed by the Thyroid Symptom Rating Questionnaire (p < 0.001). Compared with placebo, ginger also significantly improved mean scores for cold intolerance, constipation, dry skin, appetite, memory loss, and ability to concentrate, and also significantly decreased body weight and serum cholesterol levels.

Comment: Readers of the Townsend Letter know that I have concerns that many of the research studies from Iran appear to be fraudulent. There are several issues with the present study.

1. Questionable baseline data: In order to be included in the study, participants had to have a TSH level of 0.3-4.5 mIU/L. In Table 1, the mean TSH level in the ginger group was 3.62 ± 2.21 mIU/L. Assuming a Gaussian distribution of TSH values, with that mean and standard deviation, approximately 16% of the subjects in the ginger group (i.e., 4 or 5 subjects) would have had a TSH level of 5.83 or higher, which would have made them ineligible for the study. In order to be included in the study, participants also had to have a body mass index (BMI) of 19-35 kg/m². In Table 1, the mean BMI in the ginger group was 31.17 ± 5.28 kg/m². Assuming a Gaussian distribution of BMI values, with that mean and standard deviation, approximately 16% of the subjects in the ginger group (i.e., 4 or 5 subjects) would have had a BMI of 36.45 kg/m² or higher, which would have made them ineligible for the study.

2. Discrepancies regarding recruitment: The paper stated that the target sample size was 60 subjects. The Iranian Registry of Clinical Trials (IRCT) document that is associated with this paper stated that the target sample size was 120 subjects. The paper, but not the IRCT document, mentioned the use of multivitamins or the presence of vitamin D deficiency as exclusion criteria.

3. Discrepancies regarding dates: The IRCT document was registered on February 6, 2020. The document stated that recruitment was complete. However, the paper stated that the subjects were enrolled between August and November 2020.

4. Another possible issue: The 60 subjects enrolled in this study had all been referred to an endocrinology clinic, apparently because of persistent hypothyroid symptoms despite normalization of laboratory tests for thyroid function. One might reasonably assume that the purpose of such a referral would be to have the patient evaluated for other possible endocrine disorders that might be contributing to the symptoms. Patients who seek the care of a specialist are usually looking for symptom relief, not to be enrolled in a clinical trial in which they have a 50% chance of receiving a placebo and a 50% chance of receiving a treatment for which there is little or no prior evidence of efficacy. It is difficult to believe that many patients would waive their expected endocrine evaluation and instead agree to participate in this clinical trial. It is even more difficult to believe that 60 such individuals from a city of 134,000 people were enrolled in the study over a 4-month period.

Ashraf H, et al. Efficacy of ginger supplementation in relieving persistent hypothyroid symptoms in patients with controlled primary hypothyroidism: a pilot randomized, double-blind, placebo-controlled clinical trial. Evid Based Complement Alternat Med. 2022;2022:2022:5456855.

Interpreting Elevated Serum Vitamin B12 Levels

Fifty serum samples with very high levels of vitamin B12 (> 1476 pmol/L) were randomly selected to search for macro-B12 interference. Eighteen percent of the samples were found to contain macro-B12. Macro-B12 was detected with the use of a polyethylene glycol (PEG) precipitation procedure.

Comment: Elevated serum vitamin B12 levels have been seen in patients with hematologic disorders (promyelocytic leukemia, polycythemia vera, or hypereosinophilic syndrome) or liver disease. Macroforms of vitamin B12 (macro-B12) are sometimes present in serum. Such macroforms consist mainly of immunoglobulin-vitamin B12 complexes and are considered biologically inactive. Macro-B12 can interfere with the laboratory measurement of serum vitamin B12, resulting in falsely elevated levels. In the present study, nearly one-fifth of elevated vitamin B12 levels were an artifact caused by the presence of macro-B12. The authors of this study recommended that laboratories use the PEG precipitation procedure to screen for macro-B12 when the serum vitamin B12 level is elevated. Identification of this artifact would in some cases eliminate the need for unnecessary additional diagnostic tests.

Soleimani R, et al. Macro vitamin B12: an underestimated threat. Clin Chem Lab Med. 2020;58:408-415.