Chronic Disease

Harnessing Hydrogen’s Antioxidant Power to Treat Autoimmune Disease

By Carrie Decker, ND, Contributing Writer

Although hydrogen (H2) is well known as an alternative fuel, recognized as such by the Energy Policy Act of 1992, it was not until 2007 that it began to really make the scene in medicine.

Since then, there’s been an explosion of research on the use of H2 for a wide range of medical conditions. Evidence is mounting that H2 has potential benefits in the treatment of inflammatory and autoimmune conditions like psoriasis and rheumatoid arthritis.

HydrogenHydrogen was first used in a medical context in the 1940s, for the purpose of preventing decompression sickness in divers. However, it was largely impractical due to its high flammability; H2 is easily ignited at a concentration of approximately 4% in air.

In 2007, the first research using H2 dissolved in air at a concentration of less than 4%, or in a cellular nutrient medium, was published in Nature Medicine. Researchers at the Nippon Medical School, Kawasaki City, Japan, looked at the potential of H2 to minimize oxidative damage in a rodent model of brain injury. They showed that H2 is a powerful antioxidant that easily and rapidly diffuses across cell membranes (Ohsawa I, et al. Nat Med. 2007; 13(6): 688-94).

Since then, H2 has been administered in clinical studies as an inhaled gas, dissolved in water for oral delivery or for topical application, and infused into saline solution for intravenous delivery.

From human research we know that molecular H2 has the potential to improve metabolic health (Nakao A, et al. J Clin Biochem Nutr. 2012; 2: 12), fatty liver disease (Korovljev D, et al. Clin Res Hepatol Gastroenterol. 2019; [Epub ahead of print]), exercise performance (LeBaron TW, et al. J Lifestyle Med. 2019; 9(1): 36–43), and autonomic nervous system balance (Mizuno K, et al. Med Gas Res. 2017; 7(4): 247–255).

It can minimize brain damage following cerebral infarction (Ono H, et al. J Stroke Cerebrovasc Dis. 2017; 26 (11): 2587-2594), reduce the symptom burden associated with Parkinson’s disease (Yoritaka A, et al. Mov Disord. 2013; 28(6): 836-839), and minimize adverse effects of radiation therapy for liver cancer (Kang KM, et al. Med Gas Res. 2011), among many other things.

Weakness is Strength

One of the curious things we’ve learned from the recent spate of studies is that the antioxidant efficacy of H2 is related to the fact that it is a weak reducing agent, not a strong one (Matei N, et al. Med Gas Res. 2018; 8(3): 98–102). This means it preferentially reacts and neutralizes the most highly reactive and toxic oxidants (such as the hydroxyl radical [•OH] and peroxynitrite [ONOO-]), while sparing weaker but biologically necessary oxidants like nitric oxide (NO) and hydrogen peroxide (H2O2).

The antioxidant characteristics of H2, its biological effects, and its therapeutic benefits have been explored in roughly 450 recent publications reflecting over 170 different human and animal diseases. Ishihara and colleagues at the College of Life and Health Sciences, Chubu University, Japan, summarized the findings from 321 of these studies published between 2007 and 2015. In aggregate, they report that H2 treatment gives meaningful effects in essentially all organ systems (Ichihara M, et al. Med Gas Res. 2015; 5: 12).

Two years ago, Ge and colleagues at Taishan Medical University in China published a comprehensive review of the literature on H2, with detailed explanations of its various mechanisms. While they acknowledge that there are still many unanswered questions, they are firm in their conclusion that, “H2-based therapies show great promise as novel and innovative tools to prevent and treat human ailments that are currently major health burdens globally” (Ge L, et al. Oncotarget. 2017; 8(60): 102653–102673).

HPharmacokinetics

Because of its size, neutral charge, relative non-reactivity, and non-polarity, H2 readily passes through cellular membranes as well as the blood–brain barrier. Consequently, it can get into all tissues and cellular compartments.

After consumption of H2-rich water, the H2 concentration of the breath and plasma rises in a dose-dependent manner, peaking between 5 to 15 minutes after ingestion, and returning to baseline roughly 45 to 90 minutes later, depending on the amount ingested. But H2’s physiological effects are not limited to the time it remains in circulation, as has been shown in a number of studies.

For example, Hara and colleagues showed that human umbilical vein cell cultures grown in a hydrogen-rich medium were resistant to the damaging effects of one form of dioxin long after the H2 was undetectable in the medium (Hara F, et al. Circ J. 2016; 80(9): 2037-46).

The antioxidant effects of H2 are most prominent under conditions of high physiological and oxidative stress—the very situations in which we most need those effects (Ohta S. Methods Enzymol. 2015; 555: 289-317).

H2 turns on the transcription of other important antioxidants, detoxification enzymes, and proteins required for glutathione synthesis and recycling

The body always experiences some degree of oxidative stress, and actually needs mild oxidative stress in order to function properly. Naturally occurring oxidants such as NO and H2O2 trigger cellular signaling pathways and necessary processes like vasodilation. Mild physical stressors such as exercise, intermittent dietary restriction, and even mild ischemia enhance these healthy processes and generally have a beneficial effect (Mattson MP. Ageing Res Rev. 2008; 7(1): 1-7).

However, when the body is put into states of constant high stress, as is the case in severe emotional or psychological duress, during extreme physical exertion, in chronic diseases, or when undergoing invasive and toxic therapies for a condition like cancer, the endogenous responses are pushed beyond the threshold of adaptability.

It is precisely in these conditions, when oxidative stress has gone beyond the normal adaptive threshold, that many of the benefits of H2 are truly realized. Molecular hydrogen is able to reduce the excessive quantities of many of the most damaging oxidants (Sakai T, et al. Int J Mol Sci. 2019; 20(2), 456; Itoh T, et al. Biochem Biophys Res Commun. 2011; 411(1): 143-149).

In addition to reducing •OH and ONOO- radicals, H2 turns on the transcription of other important antioxidants, detoxification enzymes, and proteins required for glutathione synthesis and recycling (Buendia I, et al. Pharmacol Ther. 2016; 157: 84-104).

H2 oncotarget 08 102653 g001Numerous models of lipopolysaccharide (LPS)-induced inflammation and ischemia/reperfusion injury have shown that treatment with H2, in its various forms, helps protect against excessive inflammation and subsequent cellular and tissue injury. Treatment with Hdecreases the overproduction of proinflammatory cytokines and oxidants, including NO, interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNFα).

Given all the data describing the antioxidant and anti-inflammatory properties of H2, it is not surprising that researchers have begun looking at it in the context of autoimmune disease.

H2 for Rheumatoid Arthritis

The first publication of this nature was an open-label pilot study looking at the impact of consumption of supersaturated H2 water on patients with rheumatoid arthritis (RA). 

Twenty patients with RA drank 530 ml of water containing 4-5 parts per million molecular hydrogen daily for 4 weeks. This was followed by a 4-week washout period, and then another 4-week cycle of daily H2 water.

Fifteen of the 20 participants were either on methotrexate or abatacept, or a combination of these two drugs. The other five were not on any RA medications. No one in the study was being treated with steroid hormones.

Following each 4-week phase, the researchers measured key markers of oxidative stress as well as RA symptom burden.

They concluded that H2 “effectively reduces oxidative stress in patients with this condition,” noting that this correlated with amelioration of symptoms.

RA disease activity scores, based on assessment of 28 joints (DAS28), improved in most participants. In the first four-week treatment cycle, scores decreased in 18 of the 20 patients. By the end of the study, the average DAS28 score had decreased from a baseline mean of 3.83 to 2.26. Five of the patients achieved remissions (defined for the purpose of this study as a DAS28 < 2.3), and 4 were totally symptom-free by the end of the trial (Ishibashi T, et al. Med Gas Res. 2012; 2(1): 27).

This is not surprising given that reactive oxygen species (ROS), especially the •OH hydroxyl radical, are thought to be key drivers of the tissue damage that characterizes RA (Khojah HM, et al. Free Radic Biol Med. 2016; 97: 285-291).

One particularly interesting finding from this study was that the DAS28 score continued to improve during the four-week washout period, suggesting that the H2 treatment continued to have residual effects. Urinary 8-hydroxy-deoxyguanosine (8-OHdG) levels, a marker of DNA oxidative damage also improved not only during treatment but during the washout phase as well, remaining below the baseline through the end of the study.

It is possible that some of the longer-term effects seen with H2 are due as much to its impact on cellular signal transduction, protein activity, and genetic transcription, as to its direct antioxidant effects (Qian L, et al. Dordrecht, Netherlands: Springer; 2015).

Building on their initial pilot study, Ishibashi and colleagues studied H2-saline infusion treatment in a cohort of 24 RA patients. The participants were randomized to be treated with either 500 ml pure saline, or saline infused with H2 to a concentration of 1.6 ppm. The intravenous treatments were given daily for five consecutive days.

The DAS28 scores in the H2-treated group decreased from an average of 5.18 at baseline to 4.02 immediately after the five days of infusions. Four weeks after the final treatments, the average score was 3.74. There were no meaningful changes in DAS28 scores among the subjects getting the placebo saline infusions (Ishibashi T, et al. Int Immunopharmacol. 2014; 21(2): 468-73).

The investigators also reported statistically significant reductions in the levels of IL-6 and matrix metalloproteinase-3 (MMP-3)—two key markers of inflammation and joint damage—among the H2-treated patients. In the placebo group, these markers increased. MMP-3 is a strong predictor of joint destruction in people with RA (Yamanaka H, et al. Arthritis Rheum. 2000; 43(4): 852-58).

H2 for Psoriasis

Ishibashi’s group has also begun exploring the potential of H2 as a treatment for psoriasis. They published a series of three cases using a variety of different H2 administration techniques: inhalation, intravenous infusion of H2-saline, and oral ingestion of H2-infused water.

Regardless of the mode of delivery, the treated patients showed significant improvements in skin lesions and psoriatic arthritis symptoms. The visually-obvious clearance of lesions and the reductions of DAS28 and Psoriasis Area Severity Index (PASI) scores were accompanied by decreases in the levels of inflammatory cytokines such as TNF-α, IL-6, and IL-17 (Ishibashi T, et al. Mol Med Rep. 2015; 12: 2).

Bathing in H2-rich water also has been studied as a treatment for psoriasis. In a study of 41 psoriasis patients, H2 baths resulted in a 75% or greater improvement in the PASI score in 10 of 41 patients after eight weeks. In comparison, only 1 of 34 patients in the control group showed this level of improvement (Zhu Q, et al. Sci Rep. 2018; 8(1): 8051).

Whole-body bathing may not be practical for most psoriasis patients, but soaking a portion of the body that is most affected with psoriasis lesions in H2-rich water is not tremendously difficult and worthy of consideration.

Safety

Because H2 is produced to some extent by the bacteria normally present in the digestive tract, our bodies are routinely exposed to it.

Numerous studies using considerably higher doses than what H2-rich water provides, have shown that H2 has a very high safety profile and is not cytotoxic, even at very high concentrations (Friess SL, et al. Toxicol Appl Pharmacol. 1978; 46(3): 717-25; Nagatani K, et al. Med Gas Res. 2013; 13: 3).

In one study, researchers observed hypoglycemic episodes in an insulin-dependent patient with mitochondrial myopathy, who was treated with hydrogen-enriched water. The problem was resolved by lowering the patient’s insulin dose (Ito M, et al. Med Gas Res. 2011; 1(1): 24).

H2 has not been clinically studied as an intervention for young children or for women during pregnancy. However, animal studies in these settings have shown protective effects against disease and toxin exposure. This positive effect extends to fetal animals in utero (Nakano T, et al. J Clin Biochem Nutr. 2015; 57(3): 178–182).

The most convenient way for people to obtain the benefits of molecular hydrogen is via supplements that can release precise doses of H2 when mixed with plain water. Typically, these are effervescent tablets containing magnesium and a natural organic acid which react with water to release H2.

The concern about flammability of molecular hydrogen, which limited the medical utility of hydrogen gas in the 1940s, does not pertain to H2-rich water or to Hsupplements, because the amount of H2 in saturated or even supersaturated water is far below the flammability threshold.

With so much promising data from pilot clinical trials and animal studies, we can expect to see more clinical research on H2 for treatment of autoimmune conditions in the coming years. It is a very safe, low-cost approach, and it’s potential to give sustained benefits for weeks after cessation of the intervention is particularly exciting, as this would minimize cost and the hassle of having to take daily supplements indefinitely.

 

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Reckoning With the Deadly Impact of Junk Foods

By Kristen Schepker, Assistant Editor

A pair of recent studies linking poor diets to an increased risk of death and other alarming consequences like blindness underscore the critical importance of quality nutrition education in health care.

Gut Microbiome Study Reveals New Forms of Hypertension & Depression

By Kristen Schepker, Assistant Editor

A new study reveals previously unidentified connections between the intestinal microbiome and markers of cardiovascular and mental health. Researchers at the University of Florida discovered unique gut bacteria patterns in patients with high blood pressure, depression, and a combination of the two conditions.

Delta-Tocotrienol Reverses Metabolic Syndrome, Fatty Liver

By Janet Gulland, Contributing Writer

Twice daily supplementation with δ-tocotrienol, one of the eight isoforms of vitamin E, produced marked reductions of body mass index, triglyceride levels, markers of inflammation, and liver enzymes in a cohort of overweight patients with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD).

The Fast-Mimicking Diet & the Science of "Juventology"

By Becky Wright, Contributing Writer

New research into fasting, and specifically an approach called the Fasting Mimicking Diet (FMD), is shedding light on how to use foods and diet patterns to promote longevity and prevent or reverse degenerative diseases. It's an approach that is catching on with functional medicine practitioners—and their patients.

Confronting the Hidden Epidemic of Fatty Liver Disease

By Carrie Decker, ND, Contributing Writer

Non-Alcoholic Fatty Liver Disease (NAFLD) often goes undiagnosed because it may not be accompanied overt symptoms or by liver enzyme elevations. Clinicians who are not specifically looking for it, are not likely to detect it. But over the long term it can have devastating consequences. Fortunately, there are many botanical and nutraceutical interventions that can help.

Neurotransmitter Testing Holds Keys to Understanding Chronic Inflammation

By Decker Weiss, NMD, FASA, Contributing Writer

Clinically, we blame most chronic diseases on inflammation. Yet the ways we diagnose, measure, and monitor diseases associated with inflammation--including heart disease and cancer-- have not evolved to a truly clinically useful level. By looking upstream at neurotransmitter levels, we can gain important information about what's really happening with our patients. 

Early Childhood Trauma Raises Adolescent Obesity Risk

By Kristen Schepker, Assistant Editor

A new study shows that early childhood trauma correlates strongly with higher rates of adolescent obesity. The findings offer important insights into the complex etiology of pediatric obesity which, researchers believe, could stem partly from traumatic psychosocial factors early in life.

Using data from the statewide Minnesota Student Survey (MSS), a team of University of Minnesota researchers examined the association between adverse childhood experiences––or ACEs––and the development of overweight or obesity later in life. ACEs include physical or sexual abuse, neglect, household substance abuse, or the death or incarceration of a close relative, along with exposure to extreme violence.ace pyramid lrgACE Pyramid from the 1998 ACE Study

The investigators analyzed information collected from over 105,000 8th, 9th, and 11th grade students from across the state, making this the largest study to date of ACEs and their potential role in the etiology of obesity.

They grouped the students based on their height and weight (BMI) into one of five categories: underweight, normal weight, overweight, obese, or severely obese. They also looked at the adverse events self-reported by the kids, including physical abuse, sexual abuse, psychological abuse, familial substance abuse, domestic violence, and parental incarceration.

Controlling for other variables, they found that adolescents who had experienced at least one ACE were much more likely to be overweight, obese, or severely obese than their peers who had not experienced ACEs.

As reported in The Journal of Pediatrics, youth who experienced one adverse childhood event were 1.2 times, 1.4 times, and 1.5 times more likely, respectively, to be overweight, obese, and severely obese when compared with those who did not disclose any ACEs (Davis, L. et al. J Ped. 2019; 204: 71–76e). 

Adiposity risk also increased with the number and frequency of ACEs. Adolescents with six ACEs were respectively 1.5, 2.0, and 4.24 times as likely to be overweight, obese, and severely obese compared to students reporting no ACEs. Notably, they found no relationship between ACEs and underweight in this data set.

Child health professionals across disciplines should take note of these patterns. 

Growing Obesity Rates

Pediatric obesity rates in the US are soaring. According to the Centers for Disease Control and Prevention (CDC), the percentage of American children and adolescents affected by obesity has more than tripled since the 1970s. National Center for Health Statistics data from 2015-2016 show that nearly one in five school-aged children and adolescents aged 6 to 19 years were obese. 

Laurel Davis PhDLaurel Davis, PhD, University of MinnesotaWhile the ACE study did not examine potential mechanisms for the relationship between trauma and obesity, its lead author, Laurel Davis, PhD, research associate in the Department of Pediatrics at the University of Minnesota Medical School, said that there are likely several possible explanations––with stress being a key culprit.

"First, stress has been associated with changes in eating behaviors in both human and animal studies," she proposed. "Second, stress has significant effects of the body's hormonal and regulatory systems, particularly the hypothalamic-pituitary-adrenal (HPA) axis, which has been implicated in weight status."

"Finally," Davis said, "it's likely that the same factors in a youth's context that predispose them to ACEs also have effects on their access to nutritious food. For example, parental incarceration is associated with reductions in family income, which might cause food insecurity." Davis's team is planning future studies to evaluate some of these hypotheses.

Trauma Predicts Poor Health

A University of Minnesota research brief announcing the study indicates that, like adults, youth who are overweight or obese are at higher risk for developing additional related health problems, each with their own lifelong consequences. Depression, high blood pressure, metabolic disorders, sleep apnea, diabetes, and fatty liver disease are are just some of those conditions. 

Figuring out what causes obesity is a question that has long challenged many researchers. Particularly in children, it's easy to focus on the physical factors that contribute to weight status: diet, food quality, exercise and physical activity.

This new study sheds light on the often overlooked psychosocial determinants that play crucial roles not just in obesity, but in overall health and wellness.

The idea that trauma in the form of ACEs can drive obesity and other diseases is a relatively new one, but Davis' group is not the only one that's explored this connection. The landmark Adverse Childhood Experiences (ACE) Study, published in 1998 in the American Journal of Preventive Medicine, was the first to formally introduce the concept into the medical literature.

A collaboration between the CDC and Kaiser Permanente, this project utilized data collected in 1995–1997 from more than 9,500 Kaiser members at a San Diego clinic. Until Davis' publication this year, it was one of the nation's largest investigations of childhood traumas and their future health consequences.

In the study, physicians compared patients' reported childhood experiences of abuse and neglect against their current health status and behaviors. They identified seven core ACE categories––psychological, physical, or sexual abuse; domestic violence; living with household members who were substance abusers, mentally ill or suicidal, or ever imprisoned––and uncovered "a strong graded relationship between the breadth of exposure to abuse or household dysfunction during childhood and multiple risk factors for several of the leading causes of death in adults" (Felitti, J. et al. Am J Prev Med. 1998; 14(4): 245–258).

Patients who experienced more than one ACE were at higher risk for multiple health threats later in life, including ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease.

It's easy to focus on the physical factors that contribute to weight status: diet, food quality, exercise and physical activity. This new study sheds light on the often overlooked psychosocial determinants that play crucial roles not just in obesity, but in overall health and wellness.

These studies underscore the fact that health or illness are determined by far more than one's genetics or underlying biology alone. With regard to weight and obesity risk, forces like socioeconomic status, quality of life, and mental health conditions like depression and anxiety all have significant influence.

Hidden Danger 

The new University of Minnesota study reveals that adverse childhood events are far more prevalent than many clinicians might realize.

The authors say that their findings parallel a recent report from national surveys showing that nearly half of all US children have experienced at least one ACE. Between 40%-50% of youth in their sample who reported having overweight, obesity, or severe obesity also reported a minimum of one ACE. The more ACEs a child encounters, the higher his or her disease risk becomes. In some cases, the consequences are immediate.

"This study adds to our understanding of childhood overweight and obesity by showing that the relationship between ACEs and weight problems is evident even in adolescence," said Davis.

Prior studies exploring the associations between ACEs and obesity have mostly involved adult participants, and they generally suggest a strong association between childhood exposure to ACEs and obesity in adulthood. By utilizing anonymous reports from adolescents––which, according to Davis, are found to be highly reliable––she and her colleagues were uniquely able to clarify the impact of ACEs in the time period shortly after they actually occurred.

"The advantage of asking youth to report their ACEs is that it removes a potential source of bias: caregiver reluctance to report," she explained. Many ACEs are either perpetrated by parents––as in the case of physical or emotional abuse––or a cause of shame or stigma for the family, like mental illness or involvement in the criminal justice system. Allowing youth to directly report their own ACEs obviates this problem, Davis said.

Screening Children for ACEs

The mounting evidence from ACE studies compels health practitioners to recognize the strong relationship between ACEs and disease risk, beginning in adolescence and extending into adulthood.

With appropriate education and awareness, ACEs are both preventable and treatable.

"Doctors should be aware that ACEs have the potential to compromise health and wellbeing in childhood and throughout the lifecourse," Davis encouraged, adding that "addressing [a] patient's ACEs is a critical part of health promotion."

She also suggests that "due to the high prevalence of ACEs, clinical training programs should consider adding training in this area for new child health trainees, so that clinicians are prepared to screen for and respond to their patients' disclosure of ACEs."

Davis and her colleagues have not examined the efficacy of specific ACE assessment or treatment protocols, but they urge practitioners who work with young people to consider standardized screening for ACEs and to make referrals for appropriate psychosocial interventions as needed.

A number of ACE screening tools exist. A 2017 paper published in Academic Pediatrics identified and analyzed 14 different methods, including a new ACE measure that is now part of the larger National Survey of Children's Health (NSCH-ACEs).

"As for the types of services a physician should refer to, that is a complicated choice that should be based on a number of decisions, including but not limited to the type, timing, and severity of the ACE, the family's context and resources, their capacity to engage in services, and the types of services that are available in the community in which the child lives," Davis pointed out.

"Our most basic recommendation is that physicians work in collaboration with other professionals––social workers, community mental health workers––to connect families to appropriate services." She added that "treatments that involve children's caregivers are highly efficacious."

The CDC offers a list of ACE resources that include training materials, journal articles, and other educational tools for practitioners, families, and communities alike.

Most importantly, clinicians should be aware that "ACEs have a profound impact on both mental and physical health. Early life adversity is one of the most powerful social determinants of health across the lifecourse," Davis said. "For almost every condition for which the association has been examined, ACEs have been found to be related to poorer health." 

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