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Should we induce fever to assist healing?

Should we induce fever to assist healing?


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I am currently reading "The Fundamentals of Anatomy Physiology" 10th edition, and have found it an incredibly interesting book. I have just been reading about the lymphatic system, and the various Leukocytes and their roles. When it mentioned fever as an immune response, I was familiar with the concept: Bacteria and viruses operate very nicely at our usual body temperature, but not so well at around 39 degrees Celsius.

What I wasn't aware of was "For each 1 degree Celsius rise in body temperature, metabolic rate increases by 10 percent. Cells can move faster, and enzymatic reactions take place quicker." (Quoted from page 828 of that book).

Now that seems like a massive benefit (though I believe you could only really push 1 or 2 degrees before you start getting into dangerous territory), but I notice that fever is not present in all illnesses. Inflammation seems to induce fever through the wounded area, which makes sense.

So now for my question: Could it be beneficial to artificially induce fever in a person who has an illness if they are not already experiencing fever? I believe a few things would need to be considered (more than likely a lot more than I can think to list):

  • Increased metabolic activity would surely need a higher energy intake would it not?
  • Are there cells that are actually going to suffer from the temperature increase?
  • I'm assuming this would actually be a rather poor technique to deal with cancer as from my currently limited knowledge, it is simply a cell that is producing abnormal proteins. If this is the case, the metabolic increase would likely apply to these abnormal cells, resulting in faster proliferation. Are there other such cells/infections that will benefit from temperature increase?

Finally, what are possible downsides of long term fever if energy intake is sufficient to maintain an increased metabolic rate at these higher temperatures?


Could it be beneficial to artificially induce fever in a person who has an illness if they are not already experiencing fever?

No, not really. Pretty much the only use of hyperthermia in medicine is in the treatment of cancer. If you google "use of hyperthermia in medical treatment", you'll likely only find two kinds of hits: those for cancer treatment and those for malignant hyperthermia (a side effect of some psychotropic drugs.) The hyperthermia used to kill resistant cancer cells is high enough to destroy proteins (~113°-114°) and very localized; your entire body raised to this temperature would result in death very quickly. Lower (i.e. physiological) levers of "hyperthermia" (or hyperpyrexia) would not kill the cells.

At the turn of the century, there were many who believed in the therapeutic use of hyperthermia in the form of hot baths, hot springs, and even injection of infectious agents to produce fever(!), but the practice has fallen into disuse, probably because there were no studies which supported it.

However, hyperthermia isn't good for you; it is something to treat seriously. When the cause isn't known, the efforts used to treat it can amount to many unnecessary tests and treatments (as seen in the accident victim in the fourth reference. When it's present in a moderate amount, it can still be dangerous:

When fever occurs, many physiological stresses take place. Some of these include increased oxygen consumption as a response to increased cell metabolism, increased heart rate, increased cardiac output, increased leukocyte count, and an increased level of C-reactive protein. Oxygen consumption increases by 13% for every 1°C increase in body temperature, provided no shivering occurs. If shivering is present, oxygen consumption may increase by 100% to 200%. Some cytokines released during fever states also induce physiological stress. These cytokines can trigger accelerated muscle catabolism by causing weight loss, loss of strength, and negative nitrogen balance. Physiological stress can be manifested by decreased mental acuity, delirium, and seizures, which are more frequent in children.

It is likely beneficial in the presence of infection:

Heat shock proteins are one of the more recently studied fever-responsive proteins. These proteins are produced during fever states and are critical for cellular survival during stress. Studies suggest that these proteins may have anti-inflammatory effects by decreasing the levels of proinflammatory cytokines. Fever also triggers other beneficial effects, including an increase in the phagocytic and bacteriocidal activity of neutrophils and enhanced cytotoxic effects of lymphocytes. Some bacteria become less virulent and grow slower at the higher temperatures associated with fever. Increased levels of C-reactive protein promote phagocytic adherence to invading organisms, modulate inflammations, and encourage tissue repair.

In the absence of infection, there is no benefit to systemic elevation of temperature. For the disadvantages of continued elevated metabolic rate, one need only look at hyperthyroidism to see the deleterious effects, the worst being cardiotoxicity, even in subclinical hyperthyroidism, as well as dementia, atrial fibrillation, ventricular hypertrophy, miscarriage, perinatal morbidity and mortality, decreased exercise tolerance, etc.

Years ago, one of the most common self-inflicted illnesses was hyperthyroidism - people taking thyroid hormone replacement unnecessarily - usually because of the weight loss that occurs with elevated metabolic states. Interestingly, efforts are underway to isolste and manufacture a thyroid-hormone like substance which will cause decreased weight without cardiotoxic effects.

Hyperthermia in Cancer Treatment
HYPERPYREXIA PRODUCED BY BATHS
ARTIFICIAL FEVER IN THE TREATMENT OF GONORRHEAL OPHTHALMIA
Thyrotoxicosis in a patient with multiple trauma
Metabolic Effects of Thyroid Hormone Derivatives


Actually, hyperthermia is a known treatment for a range of diseases, including cancer.

Induced hyperthermia can be whole-body as well as local/regional and is under investigation in multiple studies (for example).


In terms of bacteria and viruses within humans, the reason the bacteria and viruses function well at normal body temperature is because it's normal. If fever were a perpetual state, the bacteria and viruses would evolve to be fit at that fever state.

There is also reason to believe that one way aging occurs is through metabolism (https://www.sciencedaily.com/releases/2011/04/110427091949.htm). Thus, perpetual fever would likely reduce life span.


Fever

Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. [1] [6] [7] There is not a single agreed-upon upper limit for normal temperature with sources using values between 40 and 42.3 °C (104.0 and 108.1 °F) in humans. [1] [2] [8] The increase in set point triggers increased muscle contractions and causes a feeling of cold or chills. [3] This results in greater heat production and efforts to conserve heat. [4] When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat. [4] Rarely a fever may trigger a febrile seizure, with this being more common in young children. [5] Fevers do not typically go higher than 41 to 42 °C (105.8 to 107.6 °F). [7]

Fever
Other namesPyrexia, febrile response, febrile [1] [2]
An analog medical thermometer showing a temperature of 38.7 °C or 101.7 °F
SpecialtyInfectious disease, pediatrics
SymptomsInitially: shivering, feeling cold, chills [3]
Later: flushed, sweating [4]
ComplicationsFebrile seizure [5]
CausesVirus, bacteria, increase in the body's temperature set point [6] [7]
Diagnostic methodTemperature > between 37.2 and 38.3 °C (99.0 and 100.9 °F) [1] [2] [8]
Differential diagnosisHyperthermia [2]
TreatmentBased on underlying cause, not required for fever itself [3] [9]
MedicationIbuprofen, paracetamol (acetaminophen) [9] [10]
FrequencyCommon [3] [11]

A fever can be caused by many medical conditions ranging from non-serious to life-threatening. [12] This includes viral, bacterial, and parasitic infections—such as influenza, the common cold, meningitis, urinary tract infections, appendicitis, COVID-19, and malaria. [12] [13] Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication, and cancer. [12] [14] It differs from hyperthermia, in that hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss. [2]

Treatment to reduce fever is generally not required. [3] [9] Treatment of associated pain and inflammation, however, may be useful and help a person rest. [9] Medications such as ibuprofen or paracetamol (acetaminophen) may help with this as well as lower temperature. [9] [10] Measures such as putting a cool damp cloth on the forehead and having a slightly warm bath are not useful and may simply make a person more uncomfortable. [9] Children younger than three months require medical attention, as might people with serious medical problems such as a compromised immune system or people with other symptoms. [15] Hyperthermia does require treatment. [3]

Fever is one of the most common medical signs. [3] It is part of about 30% of healthcare visits by children [3] and occurs in up to 75% of adults who are seriously sick. [11] While fever evolved as a defense mechanism, treating fever does not appear to worsen outcomes. [16] [17] Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as fever phobia. [3] [18]


What To Do For A Fever

Of all the concerns that parents have contacted my office about over the years, one of the most common ones has been what to do with a child's fever.

In addressing this concern, it's vital to understand that a fever serves to protect your body against infection and trauma in three major ways:

A fever stimulates your immune system into producing more white blood cells, antibodies, and a protein called interferon, all of which work to protect your body against harmful microorganisms.

By raising your body's temperature a few degrees, a fever makes it harder for invading bacteria and viruses to survive and flourish. The higher your core body temperature is, the harder it is for harmful microorganisms to survive in your body.

A fever helps to shuttle iron to your liver so that it is not readily available to fuel the growth of invading bacteria.

During a talk that I gave several years ago on the health benefits of fevers, a biology teacher in the audience mentioned that cold blooded animals like lizards will intentionally seek out warmer spots to lie on and rest to give themselves a fever when they are ill. He went on to explain that all living creatures in the animal kingdom use fevers to strengthen their immune systems when they are ill.

The most common cause of a fever is a bacterial or viral infection, the vast majority of which your body's self-healing mechanisms can conquer with proper rest and nutritional support. Heat stroke and poisoning can also cause fevers, more often in children than in adults. If you suspect that a fever is due to heatstroke or poisoning, I recommend that you go to the emergency room of your local hospital immediately.

A fever cannot cause brain damage unless it reaches 107.6 degrees Farenheit (42 degrees Celsius) and stays there for an extended period of time. Since your brain has a built-in thermostat that does not allow your core temperature to rise above 106 degrees Farenheit (41.1 C) during an infectious process, it's virtually impossible to experience brain damage from a fever caused by a bacterial or viral infection. The majority of fevers don't reach 105 (40.5 C) degrees. The highest temperature that I have encountered thus far has been 104.5 degrees Farenheit (40 C) in a 6-year old boy who had suffered a heat stroke.

A small percentage of children can sometimes experience short-lived seizures when they have a fever, called a febrile seizure. These seizures are caused by a rapid increase in body temperature, not by a specific temperature. There's no need to worry if your child experiences a febrile seizure, as they end quickly and do not leave after-effects.

Although it is usually best to allow a fever to run its course and to rely on your own self-healing mechanisms to get you well, I recommend that you seek medical attention for fevers that are accompanied by:

  • Difficulty breathing
  • Vomiting
  • A stiff neck
  • A persistent cough that lasts more than a week
  • Unexplained heaviness or weakness in your legs or arms
  • Unexplained irritability, confusion, listlessness, and any other behaviour that is out of character for you or your child

If none of the above symptoms are present, a fever is best treated by getting plenty of rest, drinking healthy liquids, eating lightly, and making sure that you are not increasing your core temperature by wearing too much clothing or using too many blankets. If a fever is preventing you from getting restful sleep, a minimal dose of acetaminophen (Tylenol) or ibuprofen (Advil or Motrin) can help reduce the fever slightly, which can help you get enough rest to possibly justify temporary use of these pain killers. If you take a dose that completely eliminates your fever, you might feel better in the moment, but you should expect to experience a longer recovery period than if you take a minimal dose or none at all. And please be aware that though the risk is very slight, there are potential negative effects to taking these medications, especially in little ones, so heed all warnings on labels and stay vigilant with symptoms.

For more information on managing fevers in children, I recommend reading How to Raise a Healthy Child in Spite of Your Doctor, by Dr. Robert Mendelsohn.


Dangers of Reducing Fever with Ibuprofen

Lest you think that you will simply switch to ibuprofen (Advil and Motrin) to bring a fever down instead of the risky Tylenol, know that NSAID painkillers carry their own set of risks for children. There is a clear link between the use of these painkillers and kidney problems.

A study published in the Journal of Pediatrics examined the number of instances of acute kidney injury (AKI) at one children&rsquos hospital over an 11-year period. The researchers found that of the 1015 patients admitted for this serious condition, 27 of the cases were due to the use of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Advil®) and naproxen (Aleve®). Most concerning, these problems occurred in the vast majority of cases (75%) despite the correct dosage being used! Children younger than five were more likely to have severe cases of acute kidney injury requiring dialysis.


A tumor can produce pyrogens, cause an infection that produces pyrogens or interfere with the normal functioning of the hypothalamus. Cancer treatments may cause a fever directly, or destroy white blood cells and weaken your immune system, making you more vulnerable to inflammation and infection. Medications such as steroids and morphine can also cause fever or affect your immune system.

Always follow the guidelines you received from your medical team. If you are not sure what they are, ask them:

  • What are the possible side effects of my cancer and treatment?
  • What side effects do I need to report to you right away?
  • What side effects require me to go to the emergency room?

In general, call your doctor if you have a fever:

  • 100.4° F (38°C) or higher.
  • With chills or shivering.
  • That does not respond to approved medications.
  • For more than 24 hours, or if it returns within 24 hours.
  • And you can’t take in, or keep in, any fluids.
  • Along with other symptoms that are new or getting worse.

Viral Interference and Interferon

Viral Interference

Generally, infection by one virus renders host cells resistant to other, superinfecting viruses. This phenomenon, called viral interference, occurs frequently in cell cultures and in animals (including humans). Although interference occurs between most viruses, it may be limited to homologous viruses under certain conditions. Some types of interference are caused by competition among different viruses for critical replicative pathways (extracellular competition for cell surface receptors, intracellular competition for biosynthetic machinery and genetic control). Similar interference may result from competition between defective (nonmultiplying) and infective viruses that may be produced concurrently. Another type of interference—the most important type in natural infections—is directed by the host cells themselves. These infected cells may respond to viral infection by producing interferon proteins, which can react with uninfected cells to render them resistant to infection by a wide variety of viruses.

Interferon

The important role played by interferon as a defense mechanism is clearly documented by three types of experimental and clinical observations: (1) for many viral infections, a strong correlation has been established between interferon production and natural recovery (2) inhibition of interferon production or action enhances the severity of infection and (3) treatment with interferon protects against infection. In addition, the interferon system is one of the earliest appearing of known host defenses, becoming operative within hours of infection.Figure 49-3 compares the early production of interferon with the level of antibody during experimental infection of humans with influenza virus. Clinical studies of interferon and its inducers have shown protection against certain viruses, including hepatitis B and C viruses, papovaviruses, rhinoviruses, and herpes simplex virus.

Figure 49-3

Production of virus, interferon, and antibody during experimental infection of humans with influenza wild-type virus. Nonspecific defenses include anatomic barriers, inhibitors, phagocytosis, fever, inflammation, and IFN. Specific defenses include antibody (more. )

Although interferon was first recognized as an extraordinarily potent antiviral agent, it was found subsequently to affect other vital cell and body functions. For example, it may enhance killing by granulocytes, macrophages, natural killer (NK) cells, and cytotoxic lymphocytes and affect the humoral immune response and the expression of cell membrane antigens and receptors. It may also lyse or inhibit the division of certain cells, influence cell differentiation, and cross-activate hormone functions such as those of epinephrine and adrenocorticotropin (ACTH). The effect of these modulations may influence many viral infections.

Interferon Production and Types

Interferon is produced de novo by cellular protein synthesis. The three types (alpha, beta, and gamma) differ both structurally and antigenically and have molecular weights ranging from 16,000 to 45,000. Interferons are secreted by the cell into the extracellular fluids (Fig. 49-4). Usually, virus-induced interferon is produced at about the same time as the viral progeny are released by the infected cell, thus protecting neighboring cells from the spreading virus.

Figure 49-4

Induction of beta interferon, alpha interferon, and gamma interferon, respectively, by foreign nucleic acids, foreign cells, and foreign antigens.

The three known types of interferon are induced by different stimuli. Beta interferon is induced by viral and other foreign nucleic acids in most body cells (fibroblasts, epithelial cells, and macrophages). This induction mechanism is illustrated inFigure 49-4 and the top portion ofFigure 49-5.

Figure 49-5

Cellular events of the induction, production, and action of interferon. Inducers of interferon react with cells to depress the interferon gene(s) (A). This leads to the production of mRNA for interferon (B). The mRNA is translated into the interferon (more. )

Alpha interferon can be induced by foreign cells, virus-infected cells, tumor cells, bacterial cells, and viral envelopes that stimulate mostly circulating dendritic cells and to a lesser degree monocytes and B lymphocytes to produce it (Fig. 49-4, middle).

Gamma interferon is produced (along with other lymphokines) by T lymphocytes induced by foreign antigens to which the T lymphocytes have been presensitized (Fig. 49-4). Mitogens for T cells may mimic this induction. Gamma interferon has several unusual properties: (1 ) it exerts greater immunomodulatory activity, including activation of macrophages, than the other interferons (2) it exerts greater lytic effects than the other interferons (3) it potentiates the actions of other interferons (4) it activates cells by a mechanism significantly different from that of the other interferons and (5) it inhibits intracellular microorganisms other than viruses (e.g., rickettsia).

The 24 genes that code for interferons alpha and the single gene for beta in humans, are located in adjacent positions on chromosome 9. The only gene for interferon gamma is found on chromosome 12. The genes for interferons alpha and beta exhibit significant homology but not with interferon gamma.

Genes for interferon alpha may be differentiated into two distinct clusters on the basis of the degree of homology. As a consequence, interferon alpha comprises two families of proteins, at least 14 of which belong to the alpha-1 type and two to the alpha-2 type (omega and tau).

Also, interferon occurs without apparent stimulation in the plasma of patients with autoimmune diseases (such as rheumatoid arthritis, disseminated lupus erythematosus and pemphigus) and in patients with advanced HIV infection. In these cases, an interferon antigenically identical to interferon alpha is present but which, unlike the latter, is partially inactivated at pH 2 (acid-labile interferon alpha). This interferon is a synergistic combination of interferons alpha (acid stable) and gamma (acid labile). Consequently, acid treatment reduces the interferon activity by inactivating the synergistic interferon gamma.

Mechanism of Action

Interferon does not inactivate viruses directly. Instead, it prevents viral replication in surrounding cells by reacting with specific receptors on the cell membranes to derepress cellular genes that encode intracellular effector antiviral proteins, which must be synthesized before virus replication can be inhibited (Figs. 49-5 and49-6). Alpha and beta interferons both bind to the same type of membrane receptor gamma interferon binds to a different receptor. The antiviral proteins probably inhibit viral multiplication by inhibiting the synthesis of essential viral proteins, but alternative or additional inhibitory mechanisms (e.g, inhibition of transcription and viral release) also occur. Viral protein synthesis may be inhibited by several biochemical alterations of cells, which may, in theory, inhibit viral replication at the different steps shown inFigure 49-6.

Figure 49-6

Molecular mechanisms of interferon antiviral actions.

It has been shown that the antiviral state may be transferred from interferon-treated cells to adjacent untreated cells without the continued presence of interferon (Fig. 49-4) this transfer mechanism may further amplify and spread the activity of the interferon system.

The interferon system is nonspecific in two ways: (1) various viral stimuli induce the same type of interferon, and (2) the same type of interferon inhibits various viruses. On the other hand, the interferon molecule is mostly specific in its action for the animal species in which it was induced: interferon produced by animals or humans generally stimulates antiviral activity only in cells of the same or closely related families (e.g., human interferon protects human and monkey cells, but not chicken cells).

Interferon During Natural Infection

The importance of interferon in the response to certain natural virus infections varies. Much depends on the effectiveness of the virus in stimulating interferon production and on its susceptibility to the antiviral action of interferon. Interferon protects solid tissues during virus infection it is also disseminated through the bloodstream during viremia, thereby protecting distant organs against the spreading infection. Cells protected against viral replication may eliminate virus by degrading the virus genome (Fig. 49-7).

Figure 49-7

Nonspecific elimination of viruses by cells.

Medical Applications

Interferons have been approved in several nations for treatment of viral infections (papillomas and condylomata, herpes simplex, and hepatitis B and C) and cancers (hairy cell leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphomas, and Kaposi's sarcoma in AIDS patients). Clinical trials also have shown effectiveness against cryoglobulinemia and thrombocytosis and maintenance of remission in multiple myeloma. Interferon beta has received governmental approval for treatment of relapsing multiple sclerosis and interferon gamma for chronic granulomatous disease. Studies of effectiveness in other viral infections and cancers are continuing, as are studies with substances capable of inducing endogenous interferon.


Fever of Unknown Origin

Postoperative Patients

Several reports have highlighted the fact that it is often difficult to identify the precise cause of postoperative fevers . In a series of 537 consecutive patients undergoing major gynecologic surgery, 211 (39%) developed postoperative fever. 35 Of 77 blood cultures performed on these patients, none was positive. Although 11 of 106 (10%) urine cultures were positive and 5 of 54 (9%) chest radiographs were abnormal, a specific pathologic process was detected in only 8% of febrile patients. In a prospective study by Kendrick and colleagues 36 of postoperative fever among 292 patients admitted to a gynecologic oncology service after abdominal or vaginal operation, 58 (20%) patients developed postoperative fever. Among 37 (16%) low-risk surgical patients developing postoperative fever, only 6 (3%) had an infection diagnosis. The majority of infections occurred within 4 days of the operative procedure and included pneumonia, vaginal cuff cellulitis, and urinary tract infection. The authors proposed that postoperative fever is common and frequently represents the response to surgically induced tissue injury with the release of pyrogenic cytokines and interleukins rather than the result of infection. Although fever is a well-recognized manifestation of some surgical procedures, most episodes are short-lived and do not meet the classic definition of FUO. Postoperative fevers generally do not require extensive diagnostic investigation for unusual causes of fever.

In another series concerned with the etiology of persistent postoperative fever in patients undergoing total joint arthroplasty, few definitive diagnoses were established, causing the authors to conclude that postoperative fever (postoperative days 1 through 5) is a normal component of the inflammatory response to this type of major surgery. 37


Should I go to the doctor if I have a temperature or a cough?

No. In the UK, the NHS advice is now that anyone with symptoms should stay at home for at least 7 days. If you live with other people, they should stay at home for at least 14 days, to avoid spreading the infection outside the home. This applies to everyone, regardless of whether they have travelled abroad.

In the UK, you should look on the dedicated coronavirus NHS 111 website for information. If you get worse or your symptoms last longer than seven days, you should call NHS 111. People will no longer be tested for the virus unless they are in hospital.

Many countries have imposed travel bans and lockdown conditions in order to try to halt the spread of the virus. You should check with your local authorities for the latest advice on seeking medical assistance.


2. Pain

Pain in the abdomen and the pelvic region typically begins within 3 hours of taking the misoprostol, once your uterus starts contracting. But it’s possible to experience cramps and pain after mifepristone.

It is quite like your period pain, and the pain is more if you usually have painful periods. 7 If you are in your 8th or 9th week of pregnancy, it is likely to hurt more than if you are in your 7th week. 8 You may even experience back pain.

Pain relief medication, like acetaminophen or ibuprofen, is safe to take. However, health authorities advise against using aspirin to manage the pain as it can increase bleeding. 9

Caution: If abdominal or back pain is so extreme that you are unable to stand up, seek immediate help from a doctor. 10


Micronutrient Information Center

Chlorophyll is the pigment that gives plants and algae their green color. Plants use chlorophyll to trap light needed for photosynthesis (1). The basic structure of chlorophyll is a porphyrin ring similar to that of heme in hemoglobin, although the central atom in chlorophyll is magnesium instead of iron. The long hydrocarbon (phytol) tail attached to the porphyrin ring makes chlorophyll fat-soluble and insoluble in water. Two different types of chlorophyll (chlorophyll a and chlorophyll b) are found in plants (Figure 1). The small difference in one of the side chains allows each type of chlorophyll to absorb light at slightly different wavelengths. Chlorophyllin is a semi-synthetic mixture of sodium copper salts derived from chlorophyll (2, 3). During the synthesis of chlorophyllin, the magnesium atom at the center of the ring is replaced with copper and the phytol tail is lost. Unlike natural chlorophyll, chlorophyllin is water-soluble. Although the content of different chlorophyllin mixtures may vary, two compounds commonly found in commercial chlorophyllin mixtures are trisodium copper chlorin e6 and disodium copper chlorin e4 (Figure 2).

Metabolism and Bioavailability

Little is known about the bioavailability and metabolism of chlorophyll or chlorophyllin. The lack of toxicity attributed to chlorophyllin led to the belief that it was poorly absorbed (4). However, significant amounts of copper chlorin e4 were measured in the plasma of humans taking chlorophyllin tablets in a controlled clinical trial, indicating that it is absorbed. More research is needed to understand the bioavailability and metabolism of natural chlorophylls and chlorin compounds in synthetic chlorophyllin.

Biological Activities

Complex formation with other molecules

Chlorophyll and chlorophyllin are able to form tight molecular complexes with certain chemicals known or suspected to cause cancer, including polycyclic aromatic hydrocarbons found in tobacco smoke (5), some heterocyclic amines found in cooked meat (6), and aflatoxin-B1 (7). The binding of chlorophyll or chlorophyllin to these potential carcinogens may interfere with gastrointestinal absorption of potential carcinogens, reducing the amount that reaches susceptible tissues (8). A recently completed study by Linus Pauling Institute investigator Professor George S. Bailey showed that chlorophyllin and chlorophyll were equally effective at blocking uptake of aflatoxin-B1 in humans, using accelerator mass spectrometry to track an ultra-low dose of the carcinogen (C Jubert et al., manuscript submitted).

Antioxidant effects

Chlorophyllin can neutralize several physically relevant oxidants in vitro (9, 10), and limited data from animal studies suggest that chlorophyllin supplementation may decrease oxidative damage induced by chemical carcinogens and radiation (11, 12).

Modification of the metabolism and detoxification of carcinogens

To initiate the development of cancer, some chemicals (procarcinogens) must first be metabolized to active carcinogens that are capable of damaging DNA or other critical molecules in susceptible tissues. Since enzymes in the cytochrome P450 family are required for the activation of some procarcinogens, inhibition of cytochrome P450 enzymes may decrease the risk of some types of chemically induced cancers. In vitro studies indicate that chlorophyllin may decrease the activity of cytochrome P450 enzymes (5, 13). Phase II biotransformation enzymes promote the elimination of potentially harmful toxins and carcinogens from the body. Limited data from animal studies indicate that chlorophyllin may increase the activity of the phase II enzyme, quinone reductase (14).

Therapeutic effects

A recent study showed that human colon cancer cells undergo cell cycle arrest after treatment with chlorophyllin (15). The mechanism involved inhibition of ribonucleotide reductase activity. Ribonucleotide reductase plays a pivotal role in DNA synthesis and repair, and is a target of currently used cancer therapeutic agents, such as hydroxyurea (15). This provides a potential new avenue for chlorophyllin in the clinical setting, sensitizing cancer cells to DNA damaging agents.

Disease Prevention

Aflatoxin-associated liver cancer

Aflatoxin-B1 (AFB1) a liver carcinogen produced by certain species of fungus, is found in moldy grains and legumes, such as corn, peanuts, and soybeans (2, 8). In hot, humid regions of Africa and Asia with improper grain storage facilities, high levels of dietary AFB1 are associated with increased risk of hepatocellular carcinoma. Moreover, the combination of hepatitis B infection and high dietary AFB1 exposure increases the risk of hepatocellular carcinoma still further. In the liver, AFB1 is metabolized to a carcinogen capable of binding DNA and causing mutations. In animal models of AFB1-induced liver cancer, administration of chlorophyllin at the same time as dietary AFB1 exposure significantly reduces AFB1-induced DNA damage in the livers of rainbow trout and rats (16-18), and dose-dependently inhibits the development of liver cancer in trout (19). One rat study found that chlorophyllin did not protect against aflatoxin-induced liver damage when given after tumor initiation (20). In addition, a recent study reported that natural chlorophyll inhibited AFB1-induced liver cancer in the rat (18).

Because of the long time period between AFB1 exposure and the development of cancer in humans, an intervention trial might require as long as 20 years to determine whether chlorophyllin supplementation can reduce the incidence of hepatocellular carcinoma in people exposed to high levels of dietary AFB1. However, a biomarker of AFB1-induced DNA damage (AFB1-N 7 -guanine) can be measured in the urine, and high urinary levels of AFB1-N 7 -guanine have been associated with significantly increased risk of developing hepatocellular carcinoma (21). In order to determine whether chlorophyllin could decrease AFB1-induced DNA damage in humans, a randomized, placebo-controlled intervention trial was conducted in 180 adults residing in a region in China where the risk of hepatocellular carcinoma is very high due to unavoidable dietary AFB1 exposure and a high prevalence of chronic hepatitis B infection (22). Participants took either 100 mg of chlorophyllin or a placebo before meals three times daily. After 16 weeks of treatment, urinary levels of AFB1-N 7 -guanine were 55% lower in those taking chlorophyllin than in those taking the placebo, suggesting that chlorophyllin supplementation before meals can substantially decrease AFB1-induced DNA damage. Although a reduction in hepatocellular carcinoma has not yet been demonstrated in humans taking chlorophyllin, scientists are hopeful that chlorophyllin supplementation will provide some protection to high-risk populations with unavoidable, dietary AFB1 exposure (8).

It is not known whether chlorophyllin will be useful in the prevention of cancers in people who are not exposed to significant levels of dietary AFB1, as is the case for most people living in the US. Many questions remain to be answered regarding the exact mechanisms of cancer prevention by chlorophyllin, the implications for the prevention of other types of cancer, and the potential for natural chlorophylls in the diet to provide cancer protection. Scientists from the Linus Pauling Institute’s Cancer Chemoprotection Program (CCP) are actively pursuing these research questions.

Therapeutic Uses of Chlorophyllin

Internal deodorant

Observations in the 1940s and 1950s that topical chlorophyllin had deodorizing effects on foul-smelling wounds led clinicians to administer chlorophyllin orally to patients with colostomies and ileostomies in order to control fecal odor (23). While early case reports indicated that chlorophyllin doses of 100-200 mg/day were effective in reducing fecal odor in ostomy patients (24, 25), at least one placebo-controlled trial found that 75 mg of oral chlorophyllin three times daily was no more effective than placebo in decreasing fecal odor assessed by colostomy patients (26). Several case reports have been published indicating that oral chlorophyllin (100-300 mg/day) decreased subjective assessments of urinary and fecal odor in incontinent patients (23, 27). Trimethylaminuria is a hereditary disorder characterized by the excretion of trimethylamine, a compound with a “fishy” or foul odor. A recent study in a small number of Japanese patients with trimethylaminuria found that oral chlorophyllin (60 mg three times daily) for three weeks significantly decreased urinary trimethylamine concentrations (28).

Wound healing

Research in the 1940s indicating that chlorophyllin slowed the growth of certain anaerobic bacteria in the test tube and accelerated the healing of experimental wounds in animals led to the use of topical chlorophyllin solutions and ointments in the treatment of persistent open wounds in humans (29). During the late 1940s and 1950s, a series of largely uncontrolled studies in patients with slow-healing wounds, such as vascular ulcers and pressure (decubitus) ulcers, reported that the application of topical chlorophyllin promoted healing more effectively than other commonly used treatments (30, 31). In the late 1950s, chlorophyllin was added to papain and urea-containing ointments used for the chemical debridement of wounds in order to reduce local inflammation, promote healing, and control odor (23). Chlorophyllin-containing papain/urea ointments are still available in the US by prescription (32). Several studies have reported that such ointments are effective in wound healing (33). Recently, a spray formulation of the papain/urea/chlorophyllin therapy has become available (34).

Sources

Chlorophylls

Chlorophylls are the most abundant pigments in plants. Dark green, leafy vegetables like spinach are rich sources of natural chlorophylls. The chlorophyll contents of selected vegetables are presented in Table 1 (35).

Table 1. Chlorophyll Content of Selected Raw Vegetables
Food Serving Chlorophyll (mg)
Spinach 1 cup 23.7
Parsley ½ cup 19.0
Cress, garden 1 cup 15.6
Green beans 1 cup 8.3
Arugula 1 cup 8.2
Leeks 1 cup 7.7
Endive 1 cup 5.2
Sugar peas 1 cup 4.8
Chinese cabbage 1 cup 4.1

Supplements

Chlorophyll

Green algae like chlorella are often marketed as supplemental sources of chlorophyll. Because natural chlorophyll is not as stable as chlorophyllin and is much more expensive, most over-the-counter chlorophyll supplements actually contain chlorophyllin.

Chlorophyllin

Oral preparations of sodium copper chlorophyllin (also called chlorophyllin copper complex) are available in supplements and as an over-the-counter drug (Derifil) used to reduce odor from colostomies or ileostomies or to reduce fecal odor due to incontinence (36). Sodium copper chlorophyllin may also be used as a color additive in foods, drugs, and cosmetics (37). Oral doses of 100-300 mg/day in three divided doses have been used to control fecal and urinary odor (see Therapeutic Uses of Chlorophyllin).

Safety

Natural chlorophylls are not known to be toxic, and no toxic effects have been attributed to chlorophyllin despite more than 50 years of clinical use in humans (8, 23, 29). When taken orally, chlorophyllin may cause green discoloration of urine or feces, or yellow or black discoloration of the tongue (38). There have also been occasional reports of diarrhea related to oral chlorophyllin use. When applied topically to wounds, chlorophyllin has been reported to cause mild burning or itching in some cases (39). Oral chlorophyllin may result in false positive results on guaiac card tests for occult blood (40). Since the safety of chlorophyll or chlorophyllin supplements has not been tested in pregnant or lactating women, they should be avoided during pregnancy and lactation.

Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in June 2009 by:
Roderick H. Dashwood, Ph.D.
Director, Cancer Chemoprotection Program, Linus Pauling Institute
Professor of Environmental & Molecular Toxicology
Leader, Environmental Mutagenesis & Carcinogenesis Core, Environmental Health Sciences Center
Oregon State University

Copyright 2004-2021 Linus Pauling Institute

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