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Iodine Redistribution During Trauma, Sepsis, and Hibernation: An Evolutionarily Conserved Response to Severe Stress

Jam

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The benefits of iodine — an element essential for life — are well established. As a key component of thyroid hormone, it prevents the congenital hypothyroidism that’s the leading preventable cause of intellectual disabilities around the world. Povidone-iodine has also been used in wound care for more than 50 years.

Now, says Dr. Mark Roth, a biochemist at Fred Hutchinson Cancer Research Center, he’s unraveled how iodine interacts with some oxygen-based molecules, reducing cells’ oxygen requirements and protecting against damaging oxygen radicals. The findings, published Oct. 1 in the journal Critical Care Explorations, reveal iodine’s key role in the body’s stress response.

“Iodine is part of a fundamental, primordial, conserved response to inflammation or stress,” explained Roth who studies “metabolic flexibility,” or how organisms from worms to humans can fine-tune their metabolic states.

Metabolically stressful situations, like an injurious car accident or serious bacterial infection, raise cells’ metabolic rates and increase their oxygen consumption. This is accompanied by inflammation and an increase in damaging reactive oxygen species like hydrogen peroxide. Iodine helps on both fronts: It decreases cells’ oxygen consumption and also defangs hydrogen peroxide, turning it into harmless molecules of oxygen and water.

Roth’s work demonstrates that our bodies respond to metabolic stress by detaching iodine atoms from thyroid hormone, freeing it to act as a shield against tissue damage caused by oxygen radicals. A preclinical study in mice showed that giving iodide prior to constricting blood flow to a muscle protects against both local and systemic inflammation-induced tissue damage.

Roth hopes the findings could someday be applied to improve the health of patients facing a tsunami of inflammation — including, perhaps, people experiencing a COVID-19-related
cytokine storm. He’s started a company, Faraday Pharmaceuticals, to test iodine’s benefits for patients facing inflammatory tissue damage, such as those undergoing heart attacks or who have undergone trauma. Roth is also collaborating with researchers in the U.S. Army to test whether iodide treatment in the field may improve outcomes for soldiers injured in combat.

Suspended animation leads to an iodized insight​

Roth’s work on iodine grew out of in his work on suspended animation, which garnered him a MacArthur Genius Grant. He showed that by using hydrogen sulfide, he could reduce oxygen consumption to the point that small animals, including worms, flies and mice, entered a state of near-metabolic shutdown. But the findings didn’t scale well to larger animals — the difference between an animation-suspending dose of sulfide and a toxic dose was too narrow for safety.
So Roth started scanning the periodic table, looking for elements with properties similar to sulfide. These included the elements selenium, bromine, and iodine. Like sulfide, these elements can affect a cell’s (and by extension, an organism’s) metabolic state. The sedating effects of bromide salts are well-known. In fact, in the late 19th and early 20th centuries physicians used them to treat seizure disorders. In some cases, doctors gave patients doses large enough to put them into a coma-like state, dubbed the “bromide sleep.” But Roth was interested in patients’ inflammation instead of their brains.
Iodine was another option. Iodine’s metabolism-calming effects mimic bromine’s, but because iodine’s larger atoms can’t enter cells as easily, it’s less potent. Most famously, iodine is attached to thyroid hormone, which is essential to cellular metabolism. People have understood for thousands of years that ingesting certain foods (now known to be rich in iodine such as seaweed) can prevent an enlarged thyroid gland, or goiter.
But historically, getting enough iodine was difficult. Before salt was iodized, goiter and intellectual disabilities related to iodine deficiency were common in the U.S. (Nowadays, the use of iodine in the dairy and baking industries means that most Americans can get adequate iodine without increasing their salt intake.)
Why should a nutrient so difficult to acquire be necessary?
Iodine’s essentiality has always been attributed to the fact that it’s an integral component of a life-giving molecule, thyroid hormone. But Roth was sure this wasn’t the whole story — it doesn’t describe what iodine itself does. He thinks he’s finally provided the chemical explanation for iodine’s essentiality to life.

Iodine protects against metabolic stress​

Roth suspected that iodine’s essentiality may be linked to the way bodies respond to stress. Thyroid hormone gets degraded under metabolically taxing situations, and this frees the attached iodine atoms in a form known as iodide. To see what role iodide could be playing during stressful conditions, Roth and his collaborators looked at what may initially seem like a random collection of sources: hibernating ground squirrels, trauma patients, and patients with sepsis. But there is a connection.
“So imagine you're a ground squirrel in the cold, a hibernating ground squirrel,” Roth said. “What you're doing is the same thing you're doing when you're having sepsis. You're trying to lay down and play dead, but not be dead.”
Arctic ground squirrels drop their metabolic rate and reduce their cells’ oxygen consumption every winter, entering a state of low metabolic function called torpor. This state is interspersed with more awake periods, called interbout arousal periods. To measure the iodide levels in the blood of Arctic ground squirrels, Drs. Michael Morrison and Akiko Iwata, the Roth Lab staff scientists who led the study, and research technician Merry Wick, worked with Dr. Kelly Drew at the University of Alaska Fairbanks. They compared blood iodide levels in active summer squirrels and torpid winter squirrels. They found that compared to squirrels during summer or early torpor, the blood iodide content of squirrels in late torpor or interbout arousal doubled or tripled.
With help from collaborator Dr. Ronald Maier at Harborview Medical Center and the University of Washington, Morrison and Iwata also compared blood iodide levels of patients with sepsis or trauma to healthy donors. They found that in sepsis patients, iodide levels were 26 times higher, and in trauma patients they were 17 times higher, than in healthy people.
This strongly suggested that iodide plays a role in the stress response — but wasn’t a smoking gun. The team then tested the effects of giving extra iodide before a metabolically taxing situation. They found that dosing mice with sodium iodide (one of the compounds used to iodize salt) prior to restricting muscular blood flow reduced inflammation-induced tissue damage.
“We’ve known for many years that stress-induced inflammation makes injuries even worse,” Maier said.
“In this study we found that iodide could provide a recyclable, effective and safe way to block damage from excessive inflammation caused by over production of oxygen radicals after injury and provides a potential therapeutic approach to enhance recovery, prevent complications, and reduce mortality in severely injured patients. The use of iodide in the clinical setting should soon be moving to clinical trials,” he added.
Roth, Morrison and Iwata published in 2018 that giving rats or pigs sodium iodide protected against reperfusion injury in a preclinical model of heart attack. They found that giving pigs sodium iodide prior to inducing a heart attack prevented the usual drop in thyroid hormone that’s associated with increased risk of death.
At the 2019 meeting of the American Heart Association, Faraday announced that a Phase 2 trial showed it’s safe to give patients undergoing heart attacks mega-doses of iodide. The study results support moving to a larger clinical trial to test efficacy, Roth said.

Iodine’s unique chemistry makes it essential​

Hydrogen peroxide damages nearby molecules by stealing their electrons. Antioxidants like vitamin C prevent this damage by voluntarily surrendering their electrons to hydrogen peroxide — only to become hungry for electrons themselves.
Iodine is different. The individual iodine molecules released from thyroid hormone each carry an extra electron. Known as iodide, this form of iodine sequentially swaps electrons with two molecules of hydrogen peroxide. It ends up where it started: as iodide, ready and able to do it all over again.
“So you get this wonderful agent that can allow you to remain rousable, as it were, in hibernation or [metabolic stress]. And yet it’s still controlling the oxygen consumption associated with inflammation,” Roth said.
He believes this atomic do-si-do explains why iodine atoms are linked to thyroid hormone. Because thyroid hormones increase oxygen consumption, they also increase inflammation and oxidative damage. Iodine’s there to balance it out. It’s also why kelp needs iodine, he said — to shield against oxidative stress caused by the UV rays that scorch it at low tide. It’s the echo of a primordial chemical dance that began in our planet’s infancy, long before the first stirrings of life.

From basic chemistry to human health​

The jump in iodide blood levels that Morrison and Roth saw in trauma and sepsis patients is enormous, suggesting a powerful biochemical response is occurring, Roth said. (In contrast, lactate levels only rise about three- to four-fold in patients experiencing organ damage.) But it will take several steps to go from the insight that iodine plays a central role in alleviating metabolic stress to improving human health.
The findings open up several avenues for further exploration. This includes determining whether a small daily dose of iodide, or a one-time megadose, provides more benefits. Roth is working with the U.S. Army to address this question.
Patients with COVID-19 are an obvious group who might benefit from an inflammation-dampening treatment — and Roth’s also helping to test that idea. With Maier, Roth is planning to test iodine levels from COVID patients to see if their levels increase similarly to trauma and sepsis patients (as he expects they will). Roth is also working with collaborators at the National Institute of Allergy and Infectious Diseases to test whether sodium iodide administration affects outcomes of animals infected with the novel coronavirus.
These strategies seek to capitalize on the normal ebb and flow between hydrogen peroxide and iodine. As inflammation edges upward, iodine reins it in — and a megadose of iodine may be needed when inflammation outpaces our bodies’ own stores.
“What you're really trying to do is oscillate. That is to say, your heartbeat, your breathing — you're sleeping, you're awake,” he said. “And when you get right down to why these things were chosen [for life], it's the fundamental oscillators of life.”
Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.
This work was funded by the Army Research Office and the National Science Foundation.
 
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Makrosky

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A.Ma.zing

Thanks Jam!!! I am abroad now but I'll read the articles once back home.
 

Jam

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DISCUSSION​

We present data showing that blood iodide increases in patients suffering from sepsis and traumatic shock and in squirrels during hibernation. Although these conditions differ in their specific stimuli (injury and infection in the cases of traumatic shock and sepsis and extreme environmental conditions in hibernation), they are similar in that they represent significant physiologic challenges of their respective organismal constancies. Many early investigators recognized the conserved nature of stress responses and hypothesized that fundamental biological details are probably shared in divergent species in response to seemingly unrelated stimuli (1,31,32). This idea set the stage for basic and clinical research on stress responses in health and disease. The increase in blood iodide in divergent species in unrelated circumstances is consistent with the idea that it plays a role in a conserved stress response.

We also showed that iodide administered at supra-normal levels improved outcome after injury and localized to the site of injured muscle tissue in mice. It is likely the increased iodide in the injured tissue came from deiodinated thyroid hormone. This idea is consistent with the fact that blood levels of both T3 and T4 decrease in many different diseases (33). This phenomenon is referred to by several different names over the last 70 years including nonthyroidal illness (NTIS), low T3, and euthyroid sick syndrome and has been associated with sepsis, trauma, heart attack, diabetes, renal insufficiency, and burns, and its extent of change correlates directly with severity of illness (33). Although the underlying mechanism of this phenomenon remains unclear, we demonstrated in a previous study that iodide administration sustains normal thyroid hormone levels during injury (22). This suggests that increasing blood iodide counteracts NTIS. Given that iodide is the product of thyroid hormone degradation by deiodinases which are upregulated in disease (34), it is logical to consider the degradation a natural stress response in which thyroid hormone is deiodinated to create iodide.


If increased blood iodide is part of a conserved stress response then what is the mechanism by which iodide improves outcome? Hydrogen peroxide plays a critical role in the establishment of the inflamed state (35) and, when over expressed, is likely to cause cell and tissue damage and disease resulting from excessive inflammation (36–40). The facts that iodide can catalytically convert hydrogen peroxide to oxygen and water (41) and administration of exogenous iodide increases antiperoxidant activity in the blood of animals after injury (22) suggest that this catalytic antiperoxidant activity is a mechanism by which iodide may improve outcome. The catalytic nature of iodide’s antioxidant activity distinguishes it from all other antioxidants. Vitamin C, Vitamin E, and other small molecule antioxidants are sacrificial reducing agents, becoming oxidized during the reactions with hydrogen peroxide and/or other reactive oxygen species and rapidly depleted during inflammatory states. Spent antioxidant products of these reactions must be rereduced before they are able to detoxify more reactive oxygen species (42). In conditions such as sepsis and trauma when the reducing power of many cells is exhausted, the accumulation of the oxidized forms of antioxidant molecules in tissues and blood hastens the accumulation of irreversible oxidative damage (43). During hibernation, the increase in blood iodide we observe could complement existing antioxidant defense pathways that minimize oxidative damage during torpor and emergence from torpor (44–46). As such, iodide redistribution to the blood could serve as a safe and synergistic compensatory response to limit damage caused by hydrogen peroxide.

The first two ERAs we found that reduce ischemia and reperfusion damage were sulfide and selenide (23,24). Both are able to effectively reduce oxygen demand in small mammals and improve survival in extreme conditions. However, they are quite toxic, and their physiologic profiles do not scale to large mammals. We then found that bromide, previously known as one of the first sedatives (47), and iodide also had similar properties (21). In contrast to sulfide and selenide, iodide is not toxic, and its ability to improve survival in life-threatening conditions did scale to large animals in preclinical studies (22). These preclinical demonstrations provided the foundation for phase I and phase II clinical safety trials of iodide in healthy human volunteers and patients suffering from ischemia and reperfusion injury to the heart (i.e., during acute myocardial infarction). In these clinical studies, exogenously administered 1 mg/kg iodide safely increased blood iodide to an average of 8,290 ng/mL, which is more than 1,400-fold greater than healthy volunteers and 84-fold greater than the blood iodide in trauma patients (48). Furthermore, although these clinical safety trials were not designed or provisioned to test efficacy, which will be tested in a phase III study beginning in 2020, trends in clinical measures suggested that iodide administration improved outcome in humans suffering from myocardial infarction. Although clinical evidence to support iodide administration during critical illness does not yet exist, clinicians show a willingness to use exogenous micronutrients as part of metabolic resuscitation (49). In the future, iodide administration may be integrated into the routine care of critically ill patients as well. Episodes of severe stress such as blunt trauma and sepsis, known to induce an intense inflammatory response fueled in large part by excessive oxidant generation and bystander cell injury and organ dysfunction, may well benefit from elevated levels of exogenous iodide during the early stages and/or ongoing activation of these destructive processes.

We hypothesize that iodine redistribution is an evolutionarily conserved life process used by diverse organisms to respond to stress
. Although we studied iodide in mammals, others have shown that brown algae (e.g., kelp) release iodide in response to hydrogen peroxide created by exposure to air and sunlight when the tide goes out (50). Likewise, moon jellyfish also concentrate iodine and use it to degrade hydrogen peroxide (51). The results presented here demonstrate that in response to significant physiologic stress, mammals increase blood iodide and that iodide supplementation improves outcome after injury. We conclude that iodide redistribution enables organisms to better tolerate stress, leading to its evolutionary selection as an essential stress response mechanism in many organisms. For these reasons, iodide may be useful as a clinical therapeutic.
 
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Makrosky

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@Jam damn... that is very refreshing research. I am quitw bored of the typical "take progrsterone aspirin and 2 liters of coffee". Love it.

It reminds me the italian doctor (Venturi) research on iodine as the primal, ancient antioxidant defense for all organisms.
 

LeeLemonoil

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@Jam damn... that is very refreshing research. I am quitw bored of the typical "take progrsterone aspirin and 2 liters of coffee". Love it.

It reminds me the italian doctor (Venturi) research on iodine as the primal, ancient antioxidant defense for all organisms.
Yup. We have some nice Threads here on that and Venturi.

Covid and politics have taken so much Energy and Focus from Science and Health topics on RPF. It sucks.
 

James b

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Very interesting, thanks. Does anyone find it odd that Ray spent five decades painting the most delicate picture of human physiology but doesn’t mention a single positive thing about iodine?
 

Jam

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Very interesting, thanks. Does anyone find it odd that Ray spent five decades painting the most delicate picture of human physiology but doesn’t mention a single positive thing about iodine?
It is very confusing. On the one hand, he seems to be way ahead of the curve in articles such as this one:


One of the best-known free radical scavenging substances that has been widely used as a drug is iodide. It has been used to treat asthma, parasites, syphilis, cancer, Graves’ disease, periodontal disease, and arteriosclerosis. Diseases that produce tissue overgrowth associated with inflammation--granulomas--have been treated with iodides, and although the iodide doesn’t necessarily kill the germ, it does help to break down and remove the granuloma. Leprosy and syphilis were among the diseases involving granulomas* that were treated in this way. In the case of tuberculosis, it has been suggested that iodides combine with unsaturated fatty acids which inhibit proteolytic enzymes, and thus allow for the removal of the abnormal tissue.

In experimental animals, iodide clearly delays the appearance of cataracts. (Buchberger, et al., 199l.)

Inflammation, edema, and free radical production are closely linked, and are produced by most things that interfere with energy production.

Endotoxin, produced by bacteria, mainly in the intestine, disrupts energy production, and promotes maladaptive inflammation. The wide spectrum of benefit that iodide has, especially in diseases with an inflammatory component, suggests first that it protects tissue by blocking free radical damage, but it also suggests the possibility that it might specifically protect against endotoxin.​


On the other hand, he makes very bizarre statements in interviews and via email, such as this one:
What to do if you don’t have a thyroid and can’t buy pharma thyroid?. Boil milk with oysters or seaweed. Creates iodinized casein, which works like thyroid hormone.

Too much iodine can cause headaches, constipation, diarrhea. Risk of thyroid cancer and hypothyroidism from years of eating iodized salt. Most Americans getting 10x too much iodine.


Iodocasein is not something I would ever recommend. It has been linked to severe cases of hyperthyroidism and myocarditis.,..
 

Makrosky

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Very interesting, thanks. Does anyone find it odd that Ray spent five decades painting the most delicate picture of human physiology but doesn’t mention a single positive thing about iodine?
That's why you have a brain and two eyes to read and come to your own conclusion. No need for Ray to know everything.
 

Jam

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Now you got my attention


On 16 September 2009, the Italian Competent Authority (AIFA) issued a Rapid Alert informing the Members States, the EMEA and the European Commission (EC) in accordance with Article 107 of Directive 2001/83/EC, as amended, of the suspension of the Marketing Authorisation of iodocasein/thiamine containing medicinal product (Antiadiposo) in its Member State, due to serious cases of hyperthyroidism and thyrotoxicosis.
 

James b

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That's why you have a brain and two eyes to read and come to your own conclusion. No need for Ray to know everything.
Recheck the phrasing of my statement. At no point did I mention that Ray’s stance on iodine was correct.
 
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Thanks for the call out to me.

Dr. Peat on Patrick Timpone talked about heating up oysters in milk, and how the casein absorbs the iodine and other minerals from the oysters and can serve as a thyroid replacement.

Dr. Peat has dissed the fad of high iodine and quite correctly I think. He has pointed out higher incidence of thyroid cancer with higher iodine consumption.

I do think that he has said potassium iodide can reduce arterial plaque. I think that potassium iodide has some great utility but I'm not one to regularly take iodine.
 
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Thanks for the call out to me.

Dr. Peat on Patrick Timpone talked about heating up oysters in milk, and how the casein absorbs the iodine and other minerals from the oysters and can serve as a thyroid replacement.

Dr. Peat has dissed the fad of high iodine and quite correctly I think. He has pointed out higher incidence of thyroid cancer with higher iodine consumption.

I do think that he has said potassium iodide can reduce arterial plaque. I think that potassium iodide has some great utility but I'm not one to regularly take iodine.
I think because iodine in salt is ionised and the thyroid gland might store the iodine en masse. Damage might be akin to a or several Xrays over time
 
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I think because iodine in salt is ionised and the thyroid gland might store the iodine en masse. Damage might be akin to a or several Xrays over time

his assertion is that the cassein can actually be a thyroid substitute, T3 or T4, not a passive source of iodine.
 

Jam

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I don't touch iodized salt with a 10-ft pole. I've posted about the subject before, it is not a healthy source of iodine.
 

Makrosky

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Recheck the phrasing of my statement. At no point did I mention that Ray’s stance on iodine was correct.
Apologies since re-reading it now my comment might have sound... unappropiate? Kind of a passive-aggressive way to say that it is normal that Ray doesn't have an extensive knowledge of every single mineral/hormone/peptide/etc... knowledge has limits.
I don't touch iodized salt with a 10-ft pole. I've posted about the subject before, it is not a healthy source of iodine.
What???? That I have missed. Please tell me more. Last time I checked iodized salt was just refined salt with added potassium iodide. What's the problem with that?
 

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