Extracellular Matrix and Adrenal FatigueInternal milieu is a conceptual term coined by 19th Century French physician Claude Bernard that refers to the internal environment of an organism. According to Bernard, the cells of our bodies live under optimal and thriving conditions because they are protected from the external world. Dramatic changes that can occur in the external environment that may deliver internal cellular insults include changes in temperature, acidity, ion concentrations, and nutrient levels. Physiologically, this internal milieu is composed of the water-based fluid compartments of our body, in particular the extracellular matrix, blood plasma and interstitial fluids that bathe our cells.


Extracellular Matrix/Interstitium

The term extracellular literally means outside the cell, which is the space where the matrix is located. The extracellular matrix (ECM) is a network of non-living tissues that provide support to cells. It is a three-dimensional network of proteins, glycosaminoglycans, and other macromolecules, forming a fluid-filled open highway system that runs throughout the body, from under the skin and between the organs. It surrounds arteries, muscles, and even the digestive and urinary tracts. Flowing through the Extracellular matrix is what is known as interstitial fluid. This fluid is interspaced between the matrix drain into the lymphatic system that runs through the body. Every organ is therefore affected by the disorder of fluid dynamics within this space. Collectively, the ECM and interstitial fluid surrounding it in the extracellular space is called the interstitium. Forward-looking researchers consider the interstitium an organ on its own, with its many important functions. In addition to structural support, it also plays a role in other very specific functions. They include cell adhesion, migration and proliferation. The shock absorption power of the ECM and its fluid offer protection for all organ systems, while allowing communications to occur. The interstitial fluid initiates crucial biochemical and biomechanical signaling critical for tissue development, differentiation and maintaining homeostasis. Signals are conveyed through membrane receptors called integrins. While the ECM is technically part of the interstitium, these two terms are often commonly used interchangeably.

The different expressions of extracellular matrix/interstitium components, integrins and other constituents contribute to the control of pituitary hormone production and is an important player influencing adrenal function via the hypothalamic-pituitary-adrenal axis.

The constituent materials within the interstitium can vary widely. Animal ECM contains protein, minerals, and fiber. The extracellular matrix of plants is constructed from cellulose. ECM provides the essential physical scaffolding for our seventy trillion internal cells to roam and thrive. It is a dynamic environment with ongoing cellular communications and dialog. The ECM within each tissue is unique in composition and topology. Biochemical and mechanical properties of each organ, such as its elasticity and strength is determined and protected by the ECM. For example, ligaments have special proteins within the ECM to allow movement, while in bone, ECM is made primarily from collagen and mineral deposits to create a strong structure.

Once considered a kind of inert goo, the ECM has been found to consist of semiconducting liquid crystals, materials known to have a variety of properties regulating transmission, storage, and processing of information. It, therefore, possesses amazing properties and presents immaculate order in function and structure. The ECM is one continuous interconnected ground substance, tying every function and every process in the living body one way or another. The reason is simple: every cell in the body is nourished via the interstitium and matrix, and all waste products of cellular metabolism pass through this ground substance, which is the actual milieu.

Extracellular Matrix and Alternative Medicine

Conventional Medicine Has a Limited Understanding of the Extracellular MatrixThe ECM has not been recognized by conventional allopathic medicine as an organ because it is so intertwined with physiological regulations that it is extremely challenging to study and research. The traditional scientific medical model to reduce one whole into smaller components for study often fails because the ECM works only as one unit and cannot be reduced. Modern medicine’s heritage comes from a linear-casual and cause-and-effect thought process. This is extremely successful in surgery and acute illness. It has largely failed in addressing chronic illness which exists in a multidimensional sphere.

It is here at the ECM where many of the alternative therapeutics exert their effect. It is in the ECM that causes and cures many of the so-called systemic and chronic illness, especially inflammatory conditions, are addressed.

The extracellular matrix can and should be considered one organ system that connects all spaces of the body. ECM provides the platform and space that acupuncture, cranial sacral therapy, qigong, and meridian highways travel within and work. It is within the ECM that much of the body’s pH is determined, and the more traditional detoxification modalities such as fasting, diet, vegetable juicing and oil flushes work. Rehabilitation of the ECM can vastly improve the outcome of chronic diseases. It is within the ECM that healing begins. Major pharmacological and surgical intervention should not be embarked before ensuring that the ECM and all related immune function have been distressed ahead of time for best clinical outcome.

The long-standing confusions about the significance of holistic and complementary therapies become clear when proper recognition is given to the extracellular matrix as a totally pervasive system, a major organ, that alternative medicine exerts its effect.

Adrenal Fatigue Syndrome and Extracellular Matrix

Chronic stress, either physical or emotional, can put the HPA axis on overdrive as mentioned previously. This leads to the adrenal glands working extra hard to put out anti-stress hormones such as cortisol. If stressors continue, the adrenal glands can become exhausted over time, leading to the condition known as Adrenal Fatigue Syndrome (AFS). There are four stages to AFS. Signs and symptoms of early stages (1 and 2) include fatigue, sugar and salt cravings, exercise intolerance and insomnia. Advance AFS (stages 3 and 4) can be incapacitating, with more severe symptoms including reactive hypoglycemia, hypotension, thyroid resistance, menses irregularity, low blood pressure, heart palpation, and low libido.

To combat AFS, the body produces more cortisol. One unintended consequence of unrelenting cortisol output is decreased ground substance mentioned previously. This usually occurs slowly. The progression is so gradual and insidious that it is often overlooked as pathological. As times goes on, reduced ECM ground matter increases internal risk of congestion with increased toxins and pollutants. The effect of long-term use of steroid medication is similar. Both stress and steroid use over time can lead to a catabolic effect on the body. Interestingly, activation of the parasympathetic nervous system by mediation or breathing has been shown to modulate the production of cortisol and thus lead to an increase in ground substance, allowing the ECM to self-heal spontaneously.


Extracellular Matrix Regulation and Breakdown

Adrenal Fatigue affects your extracellular matrixThe regulatory role played by ECM is a key factor in determining the success or failure of all biomedicine and therapeutics. To put it simply: a healthy ECM leads to a healthy body. Breakdown of the ECM therefore is a threat to good health. Disturbances of ECM regulation can simultaneously compromise homeostasis and efficacy, leading to eventual depletion of nutritional reserve leading to cellular dysfunction and ultimate organ failure.

When microbes attack the body, one of the things they assault is the extracellular matrix. Toxins secreted from bacteria and virus breaks down the ECM components. When the scaffolding of the body is damaged, cellular survival is at risk.

The ECM also serves as a backup garbage dump and septic tank for the body. The lymphatic system runs within, and when congested, as is normally the case in those with advanced Adrenal Fatigue Syndrome (AFS), toxins and metabolites diffuse throughout the extracellular space. Having a clean and healthy ECM forms the foundational base within which all cells can thrive. When the extracellular matrix is unpolluted, it optimizes organ function by facilitating cellular transport, intercellular signaling, detoxification, and rebuilding. Having a clean ECM is akin to taking a bath in a tub of clean water.

Without a continuously healthy ECM environment, few organs are allowed to function optimally. Having a healthy ECM is critical in achieving homeostasis at the most foundational level, bar none. Good health is simply not possible otherwise. When the homeostasis is disturbed, the body is susceptible to infectious agents. That is why despite having billions of microbes and bacteria cohabiting within our bodies, we do not get sick all the time unless our immune system is weak and our ECM is congested. Only when our ECM is polluted can microbes assert their toxic effects. Organisms already present in the body of a normal individual in fact cause many microbial diseases, such as candida. They become the cause of disease when a disturbance arises which upsets the equilibrium of the body to their favor.

When the ECM is congested, cellular breakdown is inevitable. The basic mechanism for decongesting the ECM is to open up and drain out pollutants and toxins so that the entire body has a less toxic burden. Along the same lines, the manual bodywork techniques such as lymphatic drainage work on the same principle to release toxic burden.


Signs and Symptoms of Extracellular Matrix Congestion

The ECM signals it is polluted and needs cleansing with subtle signs. They include:

  • Aches and pains of unknown origin
  • Migratory muscle pain
  • Increasing sensitivity to medication
  • Inability to tolerate nutritional supplements, even at low dose
  • Paradoxical reactions to nutritional supplements and medications
  • Bloating and indigestion
  • Long term unresolved headaches despite normal workup
  • History of gallbladder removal
  • History of liver infection such as hepatitis
  • History of excessive alcohol or cannabis use

Skin Rashes of Unknown Origin and Extracellular Matrix Congestion

  • Psoriasis and skin rash of unknown origin
  • Chemical sensitivities to shampoo nail polish, perfume, etc.
  • Food sensitivities, especially to corn, wheat, and diary products
  • Sensitivity to florescent lights and computer screens
  • Frequent yawning for no reason
  • Startles and agitates easily
  • A non-specific sense of something is wrong within the body
  • Increased in hyperpigmentation or hypopigmentation spots on skin that can come and go
  • Fatigue that fail to improve despite medications and rest
  • Unexplained dizziness
  • Feeling “wired and tired”
  • Eczema
  • Feeling worse during days of ovulation or menses
  • Muscle twitches
  • Water retention
  • Migraine headache
  • Unable to fall asleep after using a computer monitor or watching TV
  • Sense of nervousness under fluorescent lighting
  • A feeling of heaviness in the lower extremities without edema or structural defects
  • Frequent yawning, especially when outdoors or traveling

There is no single definitive diagnostic sign or symptom. There is no definitive laboratory test. Microscopic examination of blood under dark field microscopy provides some hints of internal terrain. Stacking of red blood cell in “rouleau” formation, for example, can point to ECM pollution and pH imbalance. Generally speaking, the more symptoms present, the higher the probability of ECM congestion. They point to a body in a state of fragile balance at best. The key to determining ECM health is a detailed history taken by an experienced clinician on the lookout for subtle signs of internal disarray.


Typical History

Consider the following typical history from a 45-year-old female with extracellular matrix congestion:

“For the last few years, I have been maintained on 5 mgs of Cortef 3 times day along with Armor thyroid and Cytomel. It has given me some energy, but the feeling is not very smooth but “hyper” at times. I am barely able to make it through most workdays and am very tired at night and on weekends. Some days are better than others, but I get fatigued and anxious easily. Overall, I seem to be going downhill.

I tried to eat a healthy diet but that does not seem to be enough. I developed food sensitivitiesto dairy and gluten. Almonds give me stomach discomfort, and too much eggs or sugar make me anxious. Every time I eat something wrong, my body punishes me. It takes me days to recover from my fatigue and anxiety. I have to eat frequently, once every 2-3 hours, in order to avoid crashes. I am now much more sensitive and restrictive on what I can and cannot eat.

I used to be an active person, but not anymore. Most of the time when I am at home, I lie on the couch and try to rest. Taking a long walk, soaking in a hot bath, having an emotional argument, or even being in the sun for a few minutes can induce my body to crash. My recovery time from these crashes are now getting longer compared to before. Even when I recover, I don’t feel like my body has returned back to baseline.

Signs and Symptoms with Adrenal Fatigue and Extracellular MatrixMy doctor and I tried all kinds of supplements, and nothing has worked long-term. Herbs, glandulars, vitamin C, Bs, amino acid, and minerals all seem to backfire after a while. Some work for a short time at the beginning, but then stop working. Others I cannot tolerate from the start. Still others, I get too stimulated. I am now unable to tolerate many of them. I am scared to take anymore supplements because I have had such bad experiences over the years. My doctor and I could not figure out why. It seems that my body is getting more and more sensitive. The harder we try, the worse it gets.

Despite many attempts to adjust my thyroid and steroid medications, my energy level seems to be stuck at the same low level and not improving. I am holding steady with medicine now, but I don’t know how long that can last and how I can continue in the future as I am still young. I have seen so many specialists, and no one can tell me what is really going on inside my body. My doctors all focus on the laboratory results. I don’t think they really understand how I feel inside. Some days I don’t feel like I need my Cortef and some days it does not seem like enough. I just keep doing it, afraid to get off, yet unwilling to stay on.

I have tried to kick start my methylation process by taking methyl folate but that only makes me more anxious. I take betaine HCL and ox bile with every meal but still feel bloated with occasional gastric cramps and diarrhea. I have to take Ambien to fall asleep because nothing else works. I continue to wake up in the middle of the night with heart palpitations and night sweats. It takes me a long time to fall back to sleep, and I wake up unrefreshed. I am also taking Xanax to assist me with the high anxiety that can come randomly for no apparent reason. On top of that, I have muscle pain, brain fog, eczema, lightheadedness on standing up, and joint pain. My menstrual cycle is irregular with no help from natural hormone replacement.

I am unable to tolerate stress. I get energy slumps almost daily, and crash easily. I have been to the Emergency Room multiple times and I hate to go back there because I know they will tell me there is nothing wrong with me and send me home.

I know something is very wrong with my body. It seems like I am in a slow-motion train wreck. There is a slow fire burning inside me and I know that one day it will blow up. I am scared because I do not know what I would do then. I have lost my zest for life, am socially withdrawn, and feel depressed. I am frustrated at my doctors, disappointed at myself, and angry at those around me for not understanding my plight. My integrative doctor does not know what else to do for me.”

Extracellular Matrix Cleansing Principles and Approaches

Extracellular Matrix Congestion and SupplementsBy the time ECM congestion is suspected, most people are already on a battery of nutritional supplements and medications yet not improving clinically. Many are in a state of worsening moderate to severe fatigue. If ECM congestion is suspected, a key principal to remember is that the extracellular cleanse should always precede intracellular detoxification by micronutrients.

Always start by taking a step back to make sure the internal ECM is unpolluted and flowing smoothly at the most foundational level of body function. The reason is simple: regardless of how good nutritional support is, limited benefit will be derived if the body is unable to assimilate and get rid of the metabolic by-products.

Due to an already fragile body by the time ECM decongestion is contemplated, it is important that the overall approach is comprehensive, gentle, slow going, and most importantly, nurturing to reduce toxic overload without triggering adrenal crashes.


Nutritional Supplementation and Medication Considerations

Adrenal Fatigue and InterstitiumFrom a nutritional supplementation perspective, a comprehensive approach should be detailed in accordance to the level of congestion present before starting a body cleansing detoxification. Supplements that may be good for liver and adrenal function is usually not well tolerated when the interstitium is congested. Sensitivities to vitamin C, B, herbs, and glandular compounds as well as medications are common. It may be necessary to temporarily reduce nutritional supplementation load carefully so as not to send the body into a crash or a state of withdraw.

Draining the ECM of pollutants, therefore, should be the primary focus, or else the release of toxins from micronutrients’ action on the cell (including vitamins, enzymes, minerals, etc.) will stimulate negative symptoms, such as skin eruptions, anxiety, aches and pain, fatigue, fever, malaise and skin rashes. Most of these are the result of inflammation.

Because most sufferers need some form of nutritional support, abrupt cessation is not recommended and should be avoided. Providing a gentle delivery system of nutrients with easy assimilation and cellular absorption without overstimulating and overburdening the liver workload should be the guiding principles. For example, gel caps or liquids and encapsulated powders should be considered for better absorption.

A thorough review of supplementation should be undertaken. In severe congestion, even relatively harmless compounds such as digestive enzymes and probiotics may be too much for the body to handle. Selected supplements can be considered, provided they are given at the right time, along with the proper delivery system and dosage. Slow drip delivery is preferred to bolus. The right nutrient at the wrong time or wrong dose will easily backfire given a fragile body with limited reserve.

Avoid traditional detoxification approaches such as liver flushes, body cleansing detoxification, and enemas, vegetable juicing, and fasting. These approaches can generate a significant amount of toxins that can overwhelm the liver and pollute the ECM. In other words, they can be “too strong” for the ECM. Intensive exercise can lead to excessive oxidative stress that can damage the ECM as well. Both should be avoided until the body is well healed and stable.

Avoid medications as much as possible because invariably they all have to be metabolized by the liver. This includes all steroidal hormones such as cortisol, testosterone, estrogen, and progesterone. Those who already on such medications should not discontinue abruptly. Antibiotics can be insulting to hepatic cells, and statin drugs commonly prescribed for lipid abnormality can damage the cytochrome P450 detoxification pathways over time, leading to sub-optimal liver function. Exposure to environmental toxins including fumes and chemicals should be curtailed. These toxins accumulate within the interstitium over time. Live in a clean and unpolluted environment with plenty of sunshine, fresh air, and clean water are sound principals to be adhered to whenever possible.


Which Tool to Use?

A woman with a lot of questions on interstitiumOne should always exercise prudence in choosing any alternative methodology. Remember in this discussion, we are dealing with an extremely weak and fragile body at a time when extensive medical workup and laboratory tests are normal. Clinically, the picture is convoluted and defies conventional medical logic. Symptoms include fatigue, insomnia, heart palpitation, anxiety, food and supplement sensitivity, low blood pressure, dizziness, and hypoglycemia, just to mention a few. With the lack of understanding of the root cause of Adrenal Fatigue Syndrome (AFS) to start, and not knowing the underlying mechanism of action of these tools, it comes as no surprise that these techniques, though clinically proven useful when properly deployed to the right subject, are universally rejected by conventional medicine. Once the stimulatory approach of conventional medicine, using tools such as hydrocortisone, testosterone, estrogen, thyroid replacement, anti-depressant, and sleeping pills has run its course, sufferers are abandoned. Sufferers at this point should not be discouraged, but instead should get educated and start “thinking out of the box”. Remember that modern medicine of the past 150 years does not hold a monopoly to the collective medical knowledge of 5000 years of civilization.

Not one tool mentioned above is superior to another because all are designed, when properly used, to perform a body cleansing detoxification for the interstitium in the background, subtly and slowly. The body is in control of how fast this can go. Our job is to facilitate that process by providing the body the necessary tools for self-healing. For best results, a personalized program using multiple tools to harness the collective synergistic effect is recommended. Proper design of such a program requires the clinician to thoroughly understand not only AFS but also each of these tools in detail as to their pros and cons. Some trial and error is necessary, even in the best of hands.


Gentle Detoxification of the Interstitium

Normal detoxification processes can do more harm than good when the interstitium is compromised. A more natural approach may help rid the body of harmful substances.

Warm water

Drinking plenty of warm water is one such natural, effective, yet gentle method. Warm water induces sweating, a method whereby toxins are eliminated and aids the liver in flushing out these toxins via the urine. Added to this, warm water increases your metabolism, thereby aiding the digestive process while helping the body maintain its electrolyte balance.

More benefits of water include keeping you hydrated, counteracting fatigue, calming your mind, and keeping your skin looking clear and fresh.

Warm water, lemon, and ginger

Lemon water and interstitiumPractitioners of Ayurvedic medicine have long used a tea made of warm water, lemon, and ginger to flush the system. Each of these three components has their own specific benefits.

Along with the benefits of warm water, ginger kick starts your digestive system and improves the circulation of nutrients throughout your system. It also helps in the elimination of toxins. Ginger may also have oxidative and anti-inflammatory properties, and can help with the following ailments:

  • It may help reduce the effects of motion sickness.
  • It may help reduce pregnancy-related vomiting and nausea.
  • It may help reduce nausea associated with chemotherapy treatment.
  • It may help reduce the pain and inflammation resulting from severe osteoarthritis.
  • It may help reduce the causes of heart disease or reduce your chances of getting a stroke. This is because it negates blood clotting and may help reduce cholesterol.
  • It may help control blood sugar levels.

Lemons are a great source of vitamin C, a powerful antioxidant that helps protect your interstitium from the damage of free radicals. It may also reduce your risk of developing heart disease or getting a stroke and may help lower blood pressure.

Furthermore, lemon has other great benefits:

  • It may improve the quality of your skin due to the antioxidant properties of vitamin C.
  • It aids the digestive process by improving your metabolism and acting as a mild laxative (helping to prevent toxic buildup).
  • It may support weight loss and improve insulin resistance.

Steamed vegetables and thick soups

Steamed vegetables and thick soups have a wealth of nutritional and health benefits. One of their greatest benefits is that they fight inflammation and promotes digestive health. During the cooking process, many of the complex compounds in vegetables are broken down into simpler forms, making nutritional absorption easier.

An added benefit is that they may help prevent kidney stones as the cooking process removes up to 87% of the oxalates that are present in foods. Oxalates are one of the contributors to kidney stone formation.

Avoid Castor Oil

While castor oil is rich in ricinoleic acid, which may have healing properties, and it has detoxification and mild laxative properties, it’s not a great choice for those with ECM issues.

Unfortunately, our clinical experience has found that it is generally too strong for most by the time the ECM is congested. Use of castor oil may actually make matters worse and trigger adrenal crashes. The weaker the body, the greater the risk. Too much oral castor oil can also cause diarrhea and dehydration. Transdermal applications carry similar risks and should also be avoided.


Tools To Avoid

Tui na therapy and interstitiumWhen an ECM body cleansing detoxification is being contemplated, it is important to remember that not all alternative tools and techniques are suitable for those in advanced AFS, especially when the body is very fragile. They should be avoided unless conducted under close supervision by an experienced clinician. These include skin brushing, moxibustion, ice therapy, tui na therapy, body manipulation, certain forms of yoga and breathing exercise, lymphatic massage, ultra violet light therapy, deep tissue massage, far infrared therapy, rifle therapy, hyperbaric oxygen therapy, hyperthermia, and ozone therapy. Needless to say, traditional detoxification techniques such as fasting, enemas, castor oil packs and flushes should be avoided during interstitium optimization because they are difficult to titrate when the body is fragile and can decompensate quickly.


Summary for a Body Cleansing Detoxification

The extracellular matrix is part of the internal milieu that bathes our cells. It provides the proper scaffolding for cells to thrive within our body. Pullulated and congested ECM is evident in advanced stages of AFS, where concurrent liver congestion and hypersensitivity to supplementation is common. The task of optimizing interstitium function should be considers as foundational priority in preparing the body for AFS recovery. Indiscriminate use of natural compounds to enhance energy and reduce fatigue without optimizing the ECM first is a common clinical mistake in the recovery process of those in late-stage AFS. Multiple tools are available, though most lack evidence-based data in the conventional medical model. Fortunately, they do provide positive clinical outcomes with no negative effects when properly supervised.


Dr. Lam’s Key Question

Yes, it is possible. Your lymph nodes are part of the extracellular matrix.

Adrenal Fatigue can affect your Extracellular Matrix

Interstitium