Dr. Ron’s Research Review – September 22, 2010

This week’s research review contains articles on vitamin A and beta-carotene; the Food-cobalamin malabsorption syndrome; ALS and folate.

Vitamin A

Beta-carotene conversion to vitamin A decreases as the dietary dose increases in humans. (Novotny, Harrison et al. 2010)

An uncommon cause of esophagitis: esophageal hyperkeratosis secondary to vitamin A deficiency (Herring, Nowicki et al. 2010)

Cobalamin

Food-cobalamin malabsorption syndrome, which has only recently been identified, is a disorder characterized by the inability to release cobalamin from food or its binding proteins. This syndrome is usually caused by atrophic gastritis, related or unrelated to Helicobacter pylori infection, and long-term ingestion of antacids and biguanides. (Dali-Youcef and Andres 2009)

Folate

Decreased level of 5-methyltetrahydrofolate: a potential biomarker for pre-symptomatic amyotrophic lateral sclerosis (Zhang, Chen et al. 2010)

Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis (Duthie 2010)

Statins

Amyotrophic lateral sclerosis-like conditions in possible association with cholesterol-lowering drugs (Golomb, Kwon et al. 2009)

Dr. Ron


Articles

Beta-carotene conversion to vitamin A decreases as the dietary dose increases in humans

            (Novotny, Harrison et al. 2010) Download

It has been suggested that high doses of beta-carotene limit its conversion to vitamin A, yet this effect has not been well established in humans. A feeding study was conducted in a randomized crossover design in which volunteers consumed 2 doses of deuterium-labeled beta-carotene on 2 occasions, with beta-carotene and vitamin A response assessed by plasma area under the concentration time curve (AUC). Seven volunteers (4 men, 3 women) consumed each of 2 doses of beta-carotene-d8 and provided serial blood samples for 37 d after each dose. beta-Carotene doses were 20 and 40 mg. Plasma beta-carotene-d8 was assessed by HPLC-MS. Plasma retinol (ROH)-d4, which was derived from the beta-carotene-d8, was evaluated by GC-MS after saponification to convert retinyl esters to ROH prior to the formation of the trimethylsilylether. The plasma AUC for beta-carotene-d8 increased 2-fold from the 20-mg dose to the 40-mg dose. The plasma AUC for ROH-d4 increased 36% from the 20-mg dose to the 40-mg dose. These results establish that, in humans, beta-carotene conversion to vitamin A decreases as the dietary dose increases.

An uncommon cause of esophagitis. Answer to the clinical challenges and images in GI question: image 1: esophageal hyperkeratosis secondary to vitamin A deficiency

            (Herring, Nowicki et al. 2010) Download

An update on cobalamin deficiency in adults

            (Dali-Youcef and Andres 2009) Download

Cobalamin (vitamin B12) deficiency is particularly common in the elderly (>65 years of age), but is often unrecognized because of its subtle clinical manifestations; although they can be potentially serious, particularly from a neuropsychiatric and hematological perspective. In the general population, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. Food-cobalamin malabsorption syndrome, which has only recently been identified, is a disorder characterized by the inability to release cobalamin from food or its binding proteins. This syndrome is usually caused by atrophic gastritis, related or unrelated to Helicobacter pylori infection, and long-term ingestion of antacids and biguanides. Besides these syndromes, mutations in genes encoding endocytic receptors involved in the ileal absorption and cellular uptake of cobalamin have been recently uncovered and explain, at least in part, the hereditary component of megaloblastic anemia. Management of cobalamin deficiency with cobalamin injections is currently well codified, but new routes of cobalamin administration (oral and nasal) are being studied, especially oral cobalamin therapy for food-cobalamin malabsorption.

Decreased level of 5-methyltetrahydrofolate: a potential biomarker for pre-symptomatic amyotrophic lateral sclerosis

(Zhang, Chen et al. 2010) Download

BACKGROUND: Several studies have reported that homocysteine (Hcy) is associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disease without special biomarkers for early diagnosis. Here, we examined the levels of Hcy, folic acid and its metabolic molecule 5-methyltetrahydrofolate (5-MTHF) in SOD1(G93A) transgenic mouse model of ALS in an attempt to determine whether the change in those molecules can be used as potential biomarkers for the disease. METHODS: According to the disease progression, SOD1(G93A) transgenic mice were divided into early stage group (30d); pre-symptom group (60d); symptom group (90d) and terminal stage group (120d). LC-MS/MS was used to measure the level of Hcy, folic acid and 5-MTHF in the plasma, spinal cord and cortex of the ALS transgenic SOD1(G93A) mice at different disease stages. Nissl staining was used to detect the motor neurons survival in the anterior horn of the spinal cord of the SOD1(G93A) mice. RESULTS: In this study, we demonstrated that the level of 5-MTHF is significantly decreased in the plasma, spinal cord and cortex at the early stages of pre-symptomatic ALS transgenic SOD1(G93A) mice while folic acid is decreased at the middle to late stages of the disease. Furthermore, we found that the level of Hcy is markedly elevated after the motor symptoms appeared in the ALS mice. CONCLUSION: Our study suggests that decreased 5-MTHF level may be a potential biomarker for the early stage of the disease in the ALS mice, which may warrant further validating study of 5-MTHF level in ALS patients.

Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis

         (Duthie 2010) Download

Inappropriate diet may contribute to one third of cancer deaths. Folates, a group of water-soluble B vitamins present in high concentrations in green, leafy vegetables, maintain DNA stability through their ability to donate one-carbon units for cellular metabolism. Folate deficiency has been implicated in the development of several cancers, including cancer of the colorectum, breast, ovary, pancreas, brain, lung and cervix. Generally, data from the majority of human studies suggest that people who habitually consume the highest level of folate, or with the highest blood folate concentrations, have a significantly reduced risk of developing colon polyps or cancer. However, an entirely protective role for folate against carcinogenesis has been questioned, and recent data indicate that an excessive intake of synthetic folic acid (from high-dose supplements or fortified foods) may increase human cancers by accelerating growth of precancerous lesions. Nonetheless, on balance, evidence from the majority of human studies indicates that dietary folate is genoprotective against colon cancer. Suboptimal folate status in humans is widespread. Folate maintains genomic stability by regulating DNA biosynthesis, repair and methylation. Folate deficiency induces and accelerates carcinogenesis by perturbing each of these processes. This review presents recent evidence describing how these mechanisms act, and interact, to modify colon cancer risk.

Amyotrophic lateral sclerosis-like conditions in possible association with cholesterol-lowering drugs: an analysis of patient reports to the University of California, San Diego (UCSD) Statin Effects Study

            (Golomb, Kwon et al. 2009) Download

BACKGROUND: While cases of amyotrophic lateral sclerosis (ALS) or ALS-like conditions have arisen in apparent association with HMG-CoA reductase inhibitors ('statins') and/or other lipid-lowering drugs (collectively termed 'statins' in this paper for brevity), additional information is needed to understand whether the connection may be causal. The University of California, San Diego (UCSD) Statin Effects Study is a patient-targeted adverse event surveillance project focused on lipid-lowering agents, whose aim is to capitalize on patient reporting to further define characteristics and natural history of statin adverse effects (AEs), and to ascertain whether a patient-targeted surveillance system might lead to presumptive identification of previously unrecognized AEs. ALS was a candidate 'new' AE identified through this process. The aim of the analysis presented here was to examine characteristics and natural history of reported statin-associated ALS-like conditions with attention to factors that may bear on the issue of causality. METHODS: For the present analysis, we focused on cases of statin-associated ALS that were reported to our study group prior to publication of a possible statin-ALS association. Of 35 identified subjects who had contacted the UCSD Statin Effects Study group to report ALS or an ALS-like condition, 18 could not be reached (e.g. contact information was no longer valid). Six were unable to participate (e.g. due to progression of their disease). Of the 11 who could be contacted and were able to participate, one declined to give informed consent. The remaining ten, with either a formal or probable diagnosis of ALS in the context of progressive muscle wasting/weakness arising in association with lipid-lowering drug therapy, completed a mail or phone survey eliciting information about ALS symptom onset and change in association with drug use/modification and development of statin-associated AEs. We reviewed findings in the context of literature on statin antioxidant/pro-oxidant balance, as well as ALS mechanisms involving oxidative stress and mitochondrial dysfunction. RESULTS: All ten subjects reported amelioration of symptoms with drug discontinuation and/or onset or exacerbation of symptoms with drug change, rechallenge or dose increase. Three subjects initiated coenzyme Q10 supplementation; all reported initial benefit. All subjects reportedly developed statin AEs (not indicative of ALS) prior to ALS symptom onset, strongly disproportionate to expectation (p < 0.001). Since this reflects induction of pro-oxidant effects from statins, these findings lend weight to a literature-supported mechanism by which induction by statins of oxidative stress with amplification of mitochondrial dysfunction, arising in a vulnerable subgroup, may propel mechanisms underlying both AEs and, more rarely, ALS. CONCLUSION: A theoretical foundation and preliminary clinical observations suggest that statins (and other lipid-lowering drugs) may rarely be associated with ALS in vulnerable individuals in whom pro-oxidant effects of statins predominate. Our observations have explanatory relevance extending to ALS causes that are not statin associated and to statin-associated neurodegenerative conditions that are not ALS. They suggest means for identification of a possible vulnerable subgroup. Indeed whether statins may, in contrast, confer ALS protection when antioxidant effects predominate merits examination.


References

Dali-Youcef, N. and E. Andres (2009). "An update on cobalamin deficiency in adults." QJM 102(1): 17-28.

Duthie, S. J. (2010). "Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis." J Inherit Metab Dis.

Golomb, B. A., E. K. Kwon, et al. (2009). "Amyotrophic lateral sclerosis-like conditions in possible association with cholesterol-lowering drugs: an analysis of patient reports to the University of California, San Diego (UCSD) Statin Effects Study." Drug Saf 32(8): 649-61.

Herring, W., M. J. Nowicki, et al. (2010). "An uncommon cause of esophagitis. Answer to the clinical challenges and images in GI question: image 1: esophageal hyperkeratosis secondary to vitamin A deficiency." Gastroenterology 139(2): e6-7.

Novotny, J. A., D. J. Harrison, et al. (2010). "Beta-carotene conversion to vitamin A decreases as the dietary dose increases in humans." J Nutr 140(5): 915-8.

Zhang, X., S. Chen, et al. (2010). "Decreased level of 5-methyltetrahydrofolate: a potential biomarker for pre-symptomatic amyotrophic lateral sclerosis." J Neurol Sci 293(1-2): 102-5.