Commentary by Thomas E. Levy, MD, JD
OMNS (Dec. 11, 2021) Vitamin C and cortisol are the two most important and most powerful naturally-occurring anti-inflammatory agents. The mechanisms of their synergistic action indicate they are literally designed by nature to interact together to optimize the antioxidant impact needed to resolve the disease-causing oxidation that always results from toxins, infections, and stress. As inflammation in a tissue is the direct result of the oxidation, metabolism, and depletion of vitamin C levels in that tissue, it is of primary concern to normalize cellular vitamin C levels as promptly and completely as possible. Quite literally, when intracellular vitamin C levels are normalized in an inflamed tissue, the inflammation is completely resolved, and the cells are once again in a non-diseased, normal state.
A focal vitamin C depletion in a tissue is the primary identifying feature of focal inflammation. Greater degrees of focal inflammation only occur with greater degrees of focal oxidative stress. As can logically be expected, focal oxidative stress rises as focal vitamin C stores are consumed and are not restored. This lack of vitamin C at sites of inflammation explains nicely why the acute immune system response to a focally inflamed tissue is initially dominated by the appearance of monocytes (Tabas et al., 2017). The monocytes have an exceptionally high concentration of vitamin C in them, the highest of all the immune cells. Relative to the plasma concentration of vitamin C, these monocytes concentrate vitamin C in their cytoplasm 80-fold (8,000%) higher than the plasma. Other immune cells also have very high intracellular levels of vitamin C (Evans et al., 1982). It appears likely that the initial role of monocytes arriving at a site of inflammation is to effectively deliver antioxidant impact in the form of vitamin C, working to promptly alleviate whatever degree of oxidative stress is present.
In many hospitalized patients with significant infections, extremely low plasma levels of vitamin C are present. When the depressed levels of vitamin C are present throughout the body and not focal, the associated increased oxidative stress is generalized and typically reflected in elevated blood levels of C-reactive protein (CRP). CRP is a reliable index of systemically increased inflammation that is always present when vitamin C levels are significantly low (Carr et al., 2017). Circulating cortisol levels are also the lowest in the most severely ill patients.
As it turns out, cortisol significantly augments the uptake of vitamin C into cells (Fujita et al., 2001; Mikirova et al., 2019). More specifically, it appears to stimulate the production of the messenger RNA needed to increase the expression of the sodium-ascorbate co-transporters (SVCTs). This works to enhance cellular vitamin C uptake needed to maximize the protection of metabolically active cells against oxidative stress (Savini et al., 2008). This is very likely the primary function of cortisol in the body, as there is nothing more important for the resolution of tissue inflammation and the resulting tissue damage than normalizing elevated levels of intracellular oxidative stress as rapidly and completely as possible by normalizing intracellular levels of vitamin C. And when intracellular levels of vitamin C are normal, cellular glutathione levels needed to protect the cell are also optimized.
General Disease Physiology
The physiology of all disease at the cellular and biomolecular level relates directly to the extent to which any of a variety of biomolecules are in the oxidized (electron-depleted) state. All pro-oxidants (toxins) ultimately inflict their damage by directly oxidizing biomolecules, or by indirectly resulting in the oxidation of those biomolecules (proteins, sugars, fats, enzymes, etc.). When biomolecules become oxidized (lose electrons) they no longer perform their normal chemical or metabolic functions. An oxidized enzyme, for example, can be completely inactive.
No toxin can cause any clinical toxicity unless biomolecules end up becoming oxidized. The unique array of biomolecules that become oxidized determines the nature of the clinical condition resulting from a given toxin exposure. There is no "disease" present in cells of the tissue involved in a given medical condition beyond the distribution of, identity of, and degree of oxidation in the biomolecules of an affected tissue. Rather than "causing" disease, the state of oxidation in an array of biomolecules IS the disease.
When antioxidants can donate electrons and restore a normal electron status back to previously oxidized biomolecules (reduction), the normal functions of these biomolecules are restored. This is the reason why sufficient antioxidant therapy, such as can be achieved by highly-dosed intravenous vitamin C, has proven to be so profoundly effective in blocking and even reversing the negative clinical impact of any toxin or poison. There exists no toxin against which vitamin C has been tested that has not been effectively neutralized (Levy, 2002).
Because of this, there is no better way to save a patient clinically poisoned by any agent than by immediately administering a sizeable intravenous infusion of sodium ascorbate. The addition of magnesium chloride to the infusion is also important to protect against sudden life-threatening arrhythmias that can occur before a sufficient number of the newly-oxidized biomolecules can be reduced and any remaining toxin is neutralized and excreted (Levy, 2019). The relationship between cortisol and vitamin C also mandates the addition of cortisol to such vitamin C infusions to optimize the rapidity and degree to which poisoned cells can normalize intracellular vitamin C. This directly and promptly reverses the abnormal increases of intracellular oxidation seen with any excessive toxin (poison or pro-oxidant) exposure.
As a practical point, then, the primary clinical point to take from the synergism of vitamin C and cortisol is the following:
Whenever cortisol is clinically indicated, its impact will be greatly enhanced by the simultaneous administration of vitamin C.
AND
Whenever vitamin C is clinically indicated, its impact will be greatly enhanced by the simultaneous administration of cortisol.
Cortisol Physiology
Cortisol, referred to as hydrocortisone when given as a medication, is a hormone known as a glucocorticoid. This type of hormone is produced in the outer portion (cortex) of the adrenal glands that sit on top of the kidneys. In addition to having a pronounced anti-inflammatory effect, a glucocorticoid increases glucose levels in the blood through a process known as gluconeogenesis in the liver. This process utilizes amino acids and other non-carbohydrate molecules to produce more glucose. When cortisol or other corticosteroids are too highly-dosed and given for too long a period of time, a state of widespread protein breakdown (catabolism with muscle wasting) can result as the proteins are converted to glucose. Furthermore, this continued stimulation of glucose production in the liver can result in higher circulating glucose levels and sometimes even frank diabetes. These effects account for some of the most significant side effects of chronic and highly-dosed steroid (e.g., prednisone, dexamethasone) therapy. "Traditionally-dosed" long-term steroid therapy would never cause problems if much lower doses were employed (20 mg of hydrocortisone or less daily), especially when given in conjunction with multigram doses of vitamin C. The chronic ingestion of high doses of steroids without the simultaneous intake (or internal production) of vitamin C is analogous to trying to shoot a high-powered gun without ammunition.
Of note, taking large enough amounts of vitamin C supplementation alone can eliminate the need for more cortisol to optimize intracellular uptake of the vitamin C. However, it is often not a practical option to administer the 50-, 75-, or 100-gram infusions needed to reach such optimal cellular vitamin C levels without the assistance of cortisol. Nevertheless, cortisol still greatly facilitates this process, and having enough cortisol in the bloodstream decreases the "wasting" of vitamin C by its elimination in the kidneys that would otherwise end up inside the cells.
Supplying the right amount of cortisol when it is chronically deficient and no longer being synthesized in normal amounts in the body is still absolutely essential to achieving optimal health, similar to the need for thyroid hormone administration when its levels are chronically low.
Even though the body might have "normal" levels of cortisol upon blood testing at different times in the day, this does not rule out that under conditions of severe stress and new infection/toxin exposure the adrenals might no longer have the capacity to produce sufficient additional amounts of cortisol to deal with that stress. In fact, succumbing to an infection is a direct indication that more cortisol (and vitamin C) was needed by the body. It has been observed that a fatigued individual with known adrenal insufficiency can readily progress to an influenza-like state of malaise and generalized aching when the cortisol level is especially low. Patients with clear-cut influenza have markedly low cortisol levels, and the lowest cortisol levels occur in the sickest patients with the highest fevers and the lowest white counts. Any acute severe infection results in the same classical symptoms associated with just very low cortisol levels, as seen in patients with acute adrenal insufficiency (Jefferies, 2004).
The potent anti-inflammatory effect of cortisol fits perfectly with its label as the anti-stress, "fight-or-flight" hormone. Physiologically, stress is effectively a surge of pro-oxidants (toxins) into the blood, whether from infection or another source. This results in a need for the body to immediately counteract or compensate with a surge of antioxidants. In a completely normal mammalian liver, vitamin C is synthesized from glucose modified by a sequence of four enzymes. However, most humans are missing the fourth enzyme due to an epigenetic defect.
Part of the "fight-or-flight" reaction to stress in the body is also supported by the release of adrenaline (epinephrine) from the inner part (medulla) of the adrenal glands. Adrenaline works to mobilize glucose from its storage form (glycogen) in the liver and muscles, and it also stimulates gluconeogenesis to further increase glucose levels (Cryer, 1993). This would appear to be important in making sure that enough glucose is available to the fully-functioning liver to make whatever amount of vitamin C is needed to deal with a severe enough acute infection or toxin insult. Of note, vitamin C supplementation has been shown to decrease circulating cortisol and adrenaline levels in athletes following stressful exercise. This is consistent with the role played by these two substances to increase vitamin C levels following any form of stress. When enough vitamin C is already present, cortisol and adrenaline are no longer as necessary in supporting the response of the body to stress, and their levels are appropriately lower (Peters et al., 2001).
Nevertheless, the natural design of this anti-stress, antitoxin effect in the body is incredibly elegant when vitamin C synthesis can occur in a completely normal liver, as is the case with many mammals. It can be summarized as follows:
- The presence of pro-oxidant pathogens or other toxins ("stress") in the blood results in
- A compensatory increased liver production of vitamin C released directly into the blood to neutralize the toxin surge, along with an accompanying reflex release of cortisol and adrenaline from the adrenal glands, which results in
- An increased uptake of the newly-synthesized vitamin C into the toxin-exposed cells by the increased presence of the cortisol in the blood, which is sustained by
- A cortisol-induced increased glucose production (gluconeogenesis) in the liver and an adrenaline-induced release of glucose from its storage forms (glycogen) which results in
- An ongoing conversion of that increased glucose production into more vitamin C production with an ongoing release of cortisol to bring the vitamin C inside the toxin-challenged cells, continuing until
- The infection is resolved and/or the toxins are fully neutralized with electrons, metabolized, and excreted.
However, in the typical human who is missing the fourth enzyme in the liver needed to synthesize more vitamin C from glucose, the cortisol has only the pre-existing vitamin C circulating in the blood available for cellular uptake. At the same time, the cortisol-induced and adrenaline-induced production of more glucose will chronically contribute to its excess presence throughout the body since it cannot be used to fuel the production of more vitamin C in the liver. Of note, a recently-discovered olive-derived polyphenol appropriately-dosed appears to help overcome this epigenetic defect, or at least to boost systemic levels of vitamin C in the body [www.formula216.com]. Regular supplementation with this product appears to be very effective in optimizing vitamin C impact in the body.
When the acute oxidative stress is due to the onset of infection and not solely due to the presence of a new toxin in the blood, the cortisol also plays an important role in killing the pathogen. By facilitating vitamin C entry into the infected cell, cortisol serves to help upregulate the Fenton reaction. This reaction utilizes the electrons supplied by the cellular vitamin C to break down the cytoplasmic hydrogen peroxide into the highly lethal hydroxyl radical, which immediately oxidizes every biomolecule it encounters, ultimately resulting in pathogen death, programmed cell death (apoptosis), and/or frank cellular rupture (Levy, 2021).
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