Shorts

briefed by Jule Klotter

Aluminum and Alzheimer’s Disease

Although industry keeps asserting that aluminum is safe and has no role in Alzheimer’s disease (AD), scientific review articles show otherwise. Aluminum is “the most abundant naturally occurring neurotoxic element to which we are exposed,” write Suriyadipta Bhattacharjee and colleagues. The aluminum content of drinking water directly correlates with the incidence of AD in epidemiologic studies. In their 2014 review articles, Bhattacharjee et al. list several research observations that support a causative link between aluminum and Alzheimer’s disease. First, aluminum “strongly promotes amyloid aggregation and accumulation” in the brain, a defining characteristic of AD. In addition, aluminum exposure increases both inflammatory signaling and the level of certain brain gene messenger RNAs and micro RNAs found in people with Alzheimer’s. Bhattacharjee and colleagues say, “Perhaps most importantly … of all pharmaceutical treatment approaches directed against AD to date, chelation using the antioxidant and trivalent iron/aluminum chelator desferrioxamine has been shown to be one of the most effective therapeutic strategies [for moderate- to late-stage AD] yet devised.”

In addition to ingesting aluminum in food and drinking water, particulate aluminum can be inhaled, moving directly to the hippocampus. Christopher Exley and Thomas Vickers present a 2014 case report of a 58-year-old man who was diagnosed with Alzheimer’s in 2003. For eight years preceding his diagnosis, the man had daily work exposure to aluminum sulfate “dust.” Initially, the man experienced headaches, fatigue, and mouth ulcers. By 1999, memory problems and depression had developed. Brain tissue samples, taken after his death at age 66, showed a mean aluminum level of 2.98µg/g dry weight in the frontal lobe – “more than three times higher than a mean value 0.83 µg/g dry weight previously recorded for multiple samples of frontal lobe from multiple individuals.” In addition, one-third of the 46 samples taken from the man’s brain had “potentially pathological” aluminum levels exceeding 3.50µg/g dry weight. Exley says that a third possible source of aluminum is vaccination and allergy immunotherapy that use aluminum adjuvants. Immune cells are known to take up aluminum adjuvant particulate after a vaccine or allergy immunotherapy injection and move the metal throughout the body and into the brain.

The body eliminates aluminum via urine and perspiration. Exley proposes using the biologically available form of silicon, silicic acid, to increase the metal’s removal from the body. “This therapy is based upon the observation that drinking silicon-rich mineral waters increases the excretion of aluminum in urine,” he writes. He discovered in the late 1990s that silicon reduced acute aluminum toxicity in fish. Exley and his colleagues have not yet verified whether silicon-rich mineral water also increases aluminum excretion through perspiration.

Bhattacharjee S, Zhao Y, Hill JM, Percy ME, Lukiw WJ. Aluminum and its potential contribution to Alzheimer’s disease. Front Aging Neurosci. 2014;6:62. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3986683. Accessed October 19, 2015.

Exley C. Why industry propaganda and political interference cannot disguise the inevitable role played by human exposure to aluminum in neurodegenerative diseases, including Alzheimer’s disease. Front Neurol. October 2014;5:212. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC4209859. Accessed July 8, 2015.

Exley C, Vickers T. Elevated brain aluminium and early onset Alzheimer’s disease in an individual occupationally exposed to aluminium: a case report. J Med Case Rep. 2014;8:41. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3923550. Accessed October 19, 2015.

Breath Analysis and VOCs

For millennia, physicians have noticed that some diseases produce characteristic breath odors. Technology now permits researchers to identify the volatile organic compounds (VOCs) that cause the odors. Researchers have identified over 3400 VOCs in deep alveolar breath, many of which result from metabolic processes throughout the body, according to a 2014 review article led by Nicholas J. W. Rattray. VOC patterns in exhaled breath potentially offer a noninvasive method for diagnosing multiple conditions. Research, however, has proceeded slowly since Linus Pauling first presented a paper on a typical human breath signature to the National Academy of Sciences in 1971, primarily because of technological challenges.

Breath analysis is quite complex. While many VOCs arise during metabolism, others come from exogenous sources such as inhalation of car exhaust or cigarette smoke or the ingestion of certain foods or beverages, explain Frank S. Cikach Jr. and Raed A. Dweik. Their 2012 review article discusses the use of breath analysis in cardiovascular illness. Protocols for reliably capturing a breath sample, technology that can detect compounds at very low concentrations, and methods for separating potential biomarkers from other signals need to be addressed before breath analysis can be used to diagnose nonpulmonary illnesses. Also, the technological hardware needs to be smaller and less complex for widespread clinical use.

In addition to solving technological issues, researchers must accurately identify the VOC patterns that correlate with targeted diseases. Rattray and colleagues say that no single VOC is likely to indicate a specific illness: “Specific combinations or classes of compounds (i.e., fingerprints) are more likely to form the basis of a ‘compound biomarker panel’ for a disease. … ”

Ibrahim A. Hanouneh and colleagues conducted a 2014 study that involved patients with alcoholic hepatitis and cirrhosis (n = 40), patients with non-alcohol-related cirrhosis with acute decompensation (n = 40), and a control group of people without liver disease (n = 43). People with chronic liver disease have “‘a distinctive musty, sweet breath odor. … ’” Hanouneh and colleagues found six compounds (2-propanol, acetaldehyde, acetone, ethanol, pentane, and trimethylamine [TMA]) with elevated levels in the patients with liver disease compared with controls. Furthermore, the patients with alcoholic hepatitis had higher mean concentrations of TMA, acetone, and pentane in their breath, compared with the other patient group or with controls (for both, p < .001). The authors report that TMA, acetone, and pentane scores of 36 or higher identified the patients with alcoholic hepatitis with 90% sensitivity and 80% specificity. In addition to aiding diagnosis, the researchers hope to eventually use breath analysis to assess severity of the disease and to monitor treatment. In the case of liver disease, biopsy – an invasive procedure with risk of complications – is the gold standard for assessing disease severity.

Breath analysis has not yet reached the stage of blood panels or urine analysis for disease detection; but once technology improves and standards for breath collection and VOC profiles are set, it may become a valuable noninvasive window into the body’s metabolic processes.

Cikach FS, Dweik RA. Cardiovascular biomarkers in exhaled breath. Prog Cardiovasc Dis. 2012;55(1):34–43. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205725. Accessed October 25, 2015.

Hanouneh IA, Zein NN, Cikach F et al. The breathprints in patients with liver disease identify novel breath biomarkers in alcoholic hepatitis. Clin Gastroenterol Hepatol. March 2014; 12(3):516–523. Available at http://europepmc.org/articles/pmc3971429. Accessed October 25, 2015.

Rattray NJW, Hamrang Z, Trivedi DK, Goodacre R, Fowler SJ. Taking your breath away: metabolomics breathes life in to personalized medicine. Trends Biotechnol. August 2014. Available at www.researchgate.net/publication/265163243. Accessed October 25, 2015.

Cost-Effectiveness

The Patient Protection and Affordable Care Act expanded the number of people with health insurance, but the cost of medical care and health insurance premiums continues to rise. Nonetheless, the US – unlike other countries – shies away from using cost-effectiveness data to make decisions about health coverage. As physician Aaron E. Carroll explains in his December 2014 editorial, one way to assess cost-effectiveness is to divide an intervention’s cost by the number of quality-adjusted life years (QALYs) it typically produces. Countries such as Britain consider QALYs and cost-effectiveness along with benefits and risks when recommending an intervention’s coverage by the National Health Service.

When passing the Affordable Care Act, US legislators refused to include cost-effectiveness measures because of concerns that looking at cost would lead to health care-rationing – that is, making hard (and unpopular) decisions about coverage. The law mandates that insurers must cover all services rated A or B by the US Preventive Services Task Force (USPSTF), without any cost sharing by consumers. In addition, insurance must cover all vaccinations recommended by the Advisory Committee on Immunization Practices (ACIP). In their analysis of effectiveness, these two agencies very rarely consider a preventive service’s cost-effectiveness. Carroll says, “That means that we are all paying for these therapies [in the form of insurance premiums], even if they are incredible inefficient.”

Moreover, the Affordable Care Act authorized the Patient Centered Outcomes Research Institute (PCORI), a nongovernmental organization, to do comparable effectiveness research. PCORI states on its website that it will not fund any proposed research that includes a formal cost-effectiveness analysis or directly compares the costs of alternative treatment approaches. The organization will fund studies that look at the effect of a treatment’s direct cost to patients, such as out-of-pocket, hardship, or barriers to care access. Apparently, insurers’ costs that get passed onto consumers via higher premiums are not an issue. As PCORI says on its website, “We don’t consider cost effectiveness to be an outcome of direct importance to patients.” Carroll says, “I think understanding how much bang for the buck I, my patients, and the public are getting from our health care spending is of great importance.”

Mark V. Pauly, Frank A. Sloan, and Sean D. Sullivan suggest that an economic advisory body could help agencies such as the USPSTF and the Advisory Committee on Immunization Practices (ACIP) consider cost-effectiveness. In making their recommendations, expert panels look solely at health benefits and risks; panel members have medical, not economic, expertise. Pauly and colleagues suggest that advisers with expertise in both health management and economics could calculate the cost per unit of additional benefit provided by a more expensive and effective alternative and compare it with a benchmark value to determine economic efficiency. Preventive services whose cost-effectiveness exceeds a to-be-determined threshold would be recommended for full insurance coverage. Other services would be available but not routinely covered by insurance. Instead, consumers would have access to information about a service’s effectiveness and cost so that they could make their own decisions. Pauly and colleagues believe that including cost-effectiveness is necessary because the costs of new drugs and the many vaccines entering the market are becoming increasingly expensive.

“If we are going to mandate that recommendations and interventions must be covered by health insurance, and if our willingness to pay the cost of this insurance is not unlimited,” says Carroll, “it seems logical that we at least consider their economic value. The cost effectiveness of a therapy need not be the only thing we use to approve coverage, but ignoring it is akin to putting our heads in the sand.”

Carroll AE. Forbidden topic in health policy debate: cost effectiveness. New York Times. December 15, 2014. Available at http://www.nytimes.com/2014/12/16/upshot/forbidden-topic-in-health-policy-debate-cost-effectiveness.html?_r=0. Accessed October 29, 2015.

Pauly MV, Sloan FA, Sullivan SD. An economic framework for preventive care advice. Health Affairs. November 2014: 33(11); 2034–2040.

Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) from a healthy donor has gained much attention as a highly effective treatment for recurrent Clostridium difficile infection. C difficile is an opportunistic infection that occurs when antibiotic therapy kills off beneficial gut bacteria, allowing C. difficile bacteria to flourish. Communities of microbes in the gut and other areas of the body are proving to have important roles in maintaining health. In a healthy person, gut microbiota actively participate in energy metabolism and immune function for the entire body. FMT is the most effective way to supply a dysfunctional gut with the hundreds of microbes that contribute to health.

Some clinicians and researchers, such as Thomas J. Borody and Alexander Khoruts, hypothesize that many conditions associated with the Western lifestyle – including constipation, IBS, IBD, neurological diseases, cardiovascular diseases, metabolic syndrome, obesity, autoimmunity, asthma, and allergies – stem from alterations in the GI microbiome. Widespread antibiotic use in medicine and in farming, a Western diet that relies on processed rather than whole foods, and farming practices that deplete beneficial soil microbes affect the composition of the GI microbiome. The effects of these alterations are just beginning to be investigated.

Because of FMT’s success in treating C. difficile, the treatment is also being studied as a possible therapy for inflammatory bowel diseases. So far, results are less consistent for irritable bowel disease, ulcerative colitis, and Crohn’s disease than for C. difficile infection (CDI). Patients with recurrent CDI often respond with just one treatment. “A systematic review of FMT in CDI from 27 countries involving over 300 cases reported excellent cure rates for relapsing CDI of around 90% via colonoscopy and enema with 76.5% cure rates via nasogastric infusion. Consequently, FMT is now a recommended treatment for the third recurrence of CDI,” report Borody, Brandt, and Paramsothy in their 2014 review. J. S. Bakken et al. published standard practice guidelines for the use of FMT in treating C. difficile infection in 2011 (http://dx.doi.org/10.1016/j.cgh.2011.08.014). Unlike those with CDI, people with other bowel conditions often require multiple treatments, and response rate is not as high. The most effective protocol for these patients still needs to be determined.

In treating patients with GI dysfunctions, researchers have observed unexpected improvements in comorbidities, suggesting that FMT may have widespread benefits. For example, neurological symptoms in three wheelchair-bound patients with multiple sclerosis greatly improved after successful FMT treatment for constipation. Urinary function returned in two patients with catheters, and all three patients regained the ability to walk (Borody TJ, Leis S, Campbell J, et al. Fecal microbiota transplantation [FMT] in multiple sclerosis. Am J Gastroenterol. 2011;106:s352.) Obese male patients in a small controlled 2012 study, led by A. Vrieze, showed significantly improved insulin sensitivity after FMT from lean donors, suggesting that GI microbiota play a major role in metabolic syndrome. Patients with chronic fatigue syndrome have also reported “persisting relief” after FMT treatment. To define the wider benefits of FMT, Borody and Khoruts say that clinical observations need to be followed by well-designed randomized trials that include systematic study of microbiota composition pre-FMT and post-FMT.

Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol. February 2012;9:88–96. Available from www.drperlmutter.com/study/fecal-microbiota-transplantation-emerging-applications. Accessed October 19, 2015.

Borody TJ, Brandt LJ, Paramsothy S. Therapeutic faecal microbiota transplantation: current status and future developments. Curr Opin Gastroenterol. 2014;30:97–105. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3868025. Accessed October 19, 2015.

Medical Cannabis Quality

Cannabis is a medicinal herb with numerous therapeutic effects. Cannabinoid compounds relieve pain, reduce nausea and vomiting, suppress muscle spasms, reduce anxiety, reduce blood sugar, promote bone growth, and have antiseizure, anti-inflammatory, neuroprotective, and anticancer effects. Like all botanicals, however, chemical content varies according to the plant’s growing, harvesting, and processing conditions as well as genetics.

To help practitioners and consumers identify high-quality medical cannabis, Americans for Safe Access has created Patient Focused Certification (PFC), a third-party certification program for the medical cannabis industry. Products and companies that gain PFC certification meet the quality standards issued by the American Herbal Products Association (AHPA) and published in the American Herbal Pharmacopeia (AHP) Cannabis monograph. Products made by a PFC-certified company have a PFC seal on their labels. PFC also provides support services to companies that cultivate, manufacture, analyze, or distribute medical cannabis products. A list of PFC-certified companies in the US is posted at http://patientfocusedcertification.org.

In addition to the certification program, Americans for Safe Access educates medical cannabis providers about government regulations and informs health care providers about legitimate clinical uses for medical cannabis. For more information, go to www.safeaccessnow.org.

Urinary Porphyrins,

Autism

In a chapter for the 2014 book Comprehensive Guide to Autism (Springer Media), Janet K. Kern, David A. Geier, Lisa Sykes, and Mark Geier discuss the use of urinary porphyrin levels to assess heavy metal toxicity in children with autism spectrum disorders (ASD). They report that 43 of 58 research articles (74%) observed a significant link between autism and one or more heavy metals, according to a 2010 review. “Moreover, eight recent studies have shown that the greater the toxic metal body burden in a child, the worse the autism,” say Kern and colleagues. Mercury, a known neurotoxin, tops the list of implicated metals; but cadmium, lead, arsenic, and aluminum have also been linked to ASD.

Although urinary porphyrins are not a direct measure of toxic metals, they can provide a way to assess body burden. (Blood testing shows only recent or ongoing metal exposure.) Some heavy metals inhibit enzymes needed for heme synthesis. This inhibition produces increased excretion of certain porphyrins (heme precursors). The types and levels of excreted porphyrins form metal-specific patterns that let doctors identify prolonged exposure to mercury, lead, arsenic, and other metals. Studies conducted on four continents have found that many children with ASD, unlike unexposed controls, show increased levels of coproporphyrin (cP) and pentacarboxyporphyrin (5cxP) and precoproporphyrin (prcP; also called keto-isocoproporphyrin) in their urine – a pattern that occurs with prolonged mercury exposure. Kern and colleagues report that chelation therapy reduces prcP and cP levels in children with autism.

“Measuring toxic metal body burden is particularly important in ASD,” write Kern et al. Children with ASD tend to have low plasma glutathione (GSH) and sulfate levels and high plasma levels of oxidized glutathione, indicating poor detoxification capacity and an overburdened detoxification system. Children with a decreased ability to remove toxins are more susceptible to damage from heavy metals.

This chapter includes guidelines for the use of urinary porphyrin testing. The authors do not recommend proceeding with detoxification until blood test levels for heavy metals are normal (indicating that ongoing exposures have been eliminated) and urinary porphyrin levels are still elevated. If porphyrin levels do not decrease with detoxification, Kern and colleagues say, “It may be important to consider other environmental/genetic factors contributing to the elevated urinary porphyrins.”

Kern JK, Geier DA, Sykes L, Geier M. Chapter 72: Urinary porphyrins in autism spectrum disorders. In: Patel VB et al., eds. Comprehensive Guide to Autism. New York: Springer; 2005:1333–1348. Available at www.researchgate.net/publication/258010236. Accessed October 25, 2015.