Dr. Ron’s Research Review – September 1, 2010

In this week’s review has articles on ALS, celiac disease, and links to two articles on SHBG.

ALS

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

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

Celiac Disease

Celiac disease: what's new about it?

         (Gasbarrini, Malandrino et al. 2008)

Digestive and nutritional considerations in celiac disease: could supplementation help?

(Malterre 2009)

Of Interest

Role of Estradiol and Sex Hormone Binding Globulin for Male Fitness and Health By Karlis Ullis, M.D.

Low Sex Hormone Binding Globulin (SHBG) Positive and Negative Effects By Karlis Ullis, M.D.

e-Journal of Age Management Medicine, August 2010 Link

Dr. Ron


Articles

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.

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.

Celiac disease: what's new about it?

            (Gasbarrini, Malandrino et al. 2008) Download

In the present review we will try to summarize the clinical and diagnostic features of celiac disease (CD) as well as the new findings on extraintestinal manifestation. CD is an immune-mediated enteropathy caused by a permanent gluten intolerance. In the last years, the diagnosis is becoming more and more frequent because of the recognition of 'new' symptoms and associated extraintestinal manifestations. Classical CD is dominated by symptoms and sequelae of gastrointestinal malabsorption. In the 'atypical forms', the extraintestinal features usually predominate, with few or no gastrointestinal symptoms. Silent CD refers to asymptomatic patients with a positive serologic test and villous atrophy on biopsy. This form is detected by screening of high-risk individuals, or villous atrophy occasionally may be detected by endoscopy and biopsy conducted for another reason. The potential form is diagnosed in groups at risk including relatives of celiac patients, Down syndrome and autoimmune diseases. Latent CD is defined by positive serological tests but not histological changes on biopsy. These individuals are asymptomatic, but later may develop symptoms and/or histological alterations. Recognition of atypical manifestations of CD is very important because many cases can remain undiagnosed with an increased risk of long-term complications.

Digestive and nutritional considerations in celiac disease: could supplementation help?

(Malterre 2009) Download

Due to the increased immune activation in the intestinal tract of people with celiac disease, the digestive and absorptive processes of those affected may be compromised. Individuals with celiac disease are more susceptible to pancreatic insufficiencies, dysbiosis, lactase insufficiencies, and folic acid, vitamin B12, iron, and vitamin D deficiencies, as well as accelerated bone loss due to an increase in inflammatory signaling molecules. Beyond strict maintenance of a gluten-free diet, research has shown benefit with additional nutritional supplementation to assist in regulation of several of these complications.

 


References

Gasbarrini, G., N. Malandrino, et al. (2008). "Celiac disease: what's new about it?" Dig Dis 26(2): 121-7.

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.

Malterre, T. (2009). "Digestive and nutritional considerations in celiac disease: could supplementation help?" Altern Med Rev 14(3): 247-57.

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.