The health disease continuum
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Objectives with this lecture:
My introduction to the healthcare system
The chronic disease epidemic
Why we’re wrong about chronic disease
Structural organization of the human body and why it matters
Abandon the classic presentation
Redefining chronic disease
Etiology of Chronic Disease and the Cell Danger Response
Gut–Mitochondria–Brain Axis
The path to healing
My introduction to the health care system.
In 2012, I graduated as a physician assistant and practiced primary care medicine for five years. I worked six days a week, 8-10 hours daily, and saw a minimum of 40 patients per day. Many patients were without insurance, exposing me to complex and unusual cases. I also spent a two-year primary care rotation as a PA student at that same clinic I would go on to work for after graduation (our program had us seeing patients after the first quarter).
Immediately after graduation, I also started Medgeeks, an organization that helps clinicians excel in school and clinical practice. We focus on clinical medicine and the day-to-day details that weren't taught in school. The goal is to help clinicians live a fulfilled life they love (in every area).
A decade later, I would be introduced to a new teacher who would push me past every physical, spiritual, emotional, and intellectual limit I thought existed. My daughter, Chloe, was born in the year 2021. At only six months of age, Chloe was diagnosed with immune thrombocytopenia. She would later develop multiple autoimmune abnormalities, and at only one year of age, she would fulfill the criteria for systemic lupus erythematosus. We would later find out she also had a primary mitochondrial disease (86% heteroplasmy) after performing whole genome sequencing. The combination of autoimmunity and mitochondrial disease meant that any organ system could be affected, which can present with any symptom imaginable.
My daughter has visited more hospitals, been examined by more doctors, and had more labs drawn than my wife and I put together throughout our entire lives. But you would never know this by looking at her. During our last rheumatology appointment, her doctor was amazed by the turn of events. She'd never seen a patient so young worsen and improve the way Chloe did. Although she may not know what happened, I assure you this was not an accident. The moment she was diagnosed, the clock started ticking, and I got to work. I
There's nothing I can write that accurately depicts the fear, sadness, and anger that constantly oscillated through my body every single day. My urgency to learn spawned out of fear that I would lose her. According to the literature, kids with this genetic mutation and with this heteroplasmy level will have neurological complications and even neurological regression during a febrile illness. During this time, ATP requirements are at an all-time high, but caloric intake is at an all-time low. Throwing in an additional variable that consumes ATP (immune dysregulation) only increases the risk of complications.
Because of this, I pushed myself harder than I ever thought I could. To be frank, I ran my body into the ground; it was unhealthy on so many levels. But I couldn't help but feel my obligation was to keep her safe; this wasn't her fault, and she didn't ask for any of this. Everyone has their version of what I went through. We all must face difficult times at some point. But, during these times, we learn and grow the most. Through the darkness, we find the light. Through fear, we find love. Through pain, we find triumph. Defining moments like this will lead to some of the most profound realizations in your life.
I've learned more in these two and a half years than my entire life. It's as if I'm in a residency, working and studying 80 hours a week, and I must immediately apply everything I'm learning—to one patient. It's no easy feat to figure out what a one-year-old is feeling or experiencing; they don't have the language to express their complex symptomology. Over time, everything started to come together. Experiencing the multiple facets of our complex medical system through a patient's eyes exposed the many flaws I never knew existed.
Patient outcomes by who's standard?
I realized health and disease exist on a complex continuum, not marked by a definitive transition point. Our current measures of disease are based on the premise that a threshold leading to signs, symptoms, and biochemical abnormalities must be reached before a name can be applied and subsequently initiate treatment. Navigating this intricate continuum is a challenge in healthcare, and we must reevaluate what truly matters for patients.
While most of us understand this intuitively, we often overlook it when dealing with patients. We all know individuals who have felt awful, yet they're assured they are perfectly healthy, only for a diagnosed disease to emerge years later. Conversely, many feel well but have alarming laboratory values that come with a diagnosis.
Our current system is binary; you either have a disease or don't. While convenient, it can lead to oversights. It simplifies decision-making and defines the standard of care, but it's not always aligned with optimal health care. It may facilitate clear insurance coverage and reimbursement benchmarks but does not equate to optimal patient outcomes; patients and clinicians often have very different definitions regarding an optimal outcome.
I always found it odd that a physician would spend 11 years (minimum) understanding the intricacies of the human body, only to be told how to practice once they entered the hospital system. The truth is, I never thought there was anything wrong with this. On the contrary, I used to believe this made for a better system. I used to believe this allowed everyone to get the same care across the country. I had the false impression that personalization was only necessary for extreme situations or those who failed the predetermined algorithm.
However, after taking my daughter to the 5th hospital and talking to countless physicians within that system, I realized that everyone gave the same canned answers. Every physician could recite what is “normally” done, the order in which it is done, and statistical outcomes. I was asked the same questions and saw the same half-hazard physical exam being done on my daughter. It's sad, but my daughter could have been replaced with any other two-year-old, and I don't believe the sequence of events would have changed. This was the first time I ever questioned the concept of disease.
At some point, clinicians stopped questioning and assumed everything taught was fact. Students were taught early on about the hierarchy in medicine. There's so much information to learn; there's no time to question everything. I admit this has improved tremendously over the years, but it wasn't too long ago that residents were forced to work 100-hour weeks and pimped to the point of humiliation. Depending on the source you look at, 40 to 60 percent of clinicians will burn out at some point in their careers. This is a big deal. The effects of burnout (to name a few):
Decreased quality of care
Poor patient satisfaction: decreased trust from the patient also increases the chance that they don't adhere to a plan. I know I wouldn't listen to someone I don't trust
Medical errors
High clinician turnover
Relationship difficulties: colleagues, patients, admin, spouse, children, parents, and friends
Substance abuse
Suicide: physicians die by suicide at twice the rate as non-physicians
We often forget that the people who created these guidelines have flaws like the rest of us. They are also overworked and burned out. It's important to remember that having the qualifications for a job doesn't make them infallible. The system is broken for everyone involved. Sadly, guidelines and policies (whether the clinician agrees with them) must be followed for employment, to avoid litigation, or for reimbursement.
At first, I wasn't sure if I was exchanging one bias for another because of my circumstances. I questioned myself. After all, multiple experts across the country gave me the same message. They all thought the same, and I was the one who thought differently. Therefore, I kept thinking I must be wrong; they surely know something I don't. This self-doubt kept rearing its ugly head. It's tough to change a belief system, especially a belief that partially defined who I was. Orson Scott Card said, “We question all our beliefs, except for the ones that we truly believe in, and those we never think to question.”
Then I read that, on average, a patient will see more than eight physicians before being diagnosed with a mitochondrial disease. Remember that this statistic only applies to patients who eventually receive an accurate diagnosis. But what about patients who stop looking for answers after the fifth doctor because they are told "it's all in their head”? What about a patient suffering from chronic migraines whose search for answers stops with prophylactic migraine therapy? What about the patient who dies after a stroke due to an underlying mitochondrial disease?
One could argue that mitochondrial disease is rare and these are outliers. But how can we confidently say that if we only test patients with a classic presentation, knowing that the classic presentation is only recognized based on confirmed cases? This is classic confirmation bias. Even so, do their lives not matter? Perhaps it's easier to sacrifice a few lives than to change a system. No one likes change.
Sometimes, it's not a matter of doing things we like but of doing the right things.
Before I became vocal, I wanted to know how far this rabbit hole went. I didn't want to isolate this to what most would consider a rare disease, and I wanted to know how far this rabbit hole went. Is this system failing people with diseases we deem common? According to the CDC, 60% of adults in the United States have at least one chronic disease, 40% have at least two or more chronic diseases, and 70% of all deaths are secondary to chronic disease. It's estimated that 80% of chronic diseases and premature deaths could potentially be prevented. According to the National Council on Aging, nearly 95% of adults 60 and older have at least one chronic condition, while almost 80% have two or more. Finally, the CDC states that 40% of school-aged children in the United States are living with at least one chronic disease; that percentage jumps to 60% if we include behavioral mental health disorders.
As it stands, 60% of adults and 60% of school-aged children all have at least one chronic disease.
As if that weren't enough, our life expectancy in the United States has slowly declined over the last few years (data from the CDC):
1900 = 47 years
1950 = 68 years
1960 = 69 years
1970 = 70 years
1980 = 73 years
1990 = 75 years
2000 = 77 years
2010 = 78 years
2019 = 79 years
2020 = 77 years
2021 = 76 years
The CDC has yet to publish any data after 2021, but a few sources I've seen show an uptick. With all the advances in medicine, it's mind-blowing to see an increase of only six years in life over the last 50 years (1970 - 1921).
We have excelled at saving lives from acute illness, infection, or traumatic injury. But what we are doing for patients with chronic disease isn't working. In part, this has to do with how we define disease.
We were wrong about chronic disease.
A chronic disease is typically considered to be any disease lasting more than 12 months.
Type 2 diabetes is a perfect example of the continuum between health and disease. Mostly, everyone is screened during their yearly physical through fasting glucose.
Prediabetes is defined with fasting glucose levels between 100 mg/dL to 125 mg/dL or an HbA1C between 5.7% to 6.4%.
Diabetes is defined when fasting glucose levels exceed 125 mg/dL or with a HbA1C of at least 6.5%.
Many think of prediabetes as the initial stages of diabetes. However, we must realize this is not the beginning of dysfunction. This is only the abnormal lab we chose to look for that appears right before the arbitrary cutoff of 125 mg/dL; other abnormalities occur long before we see an elevated fasting glucose.
Before an elevation in fasting glucose, we'll see elevated postprandial glucose and elevations in fasting and postprandial insulin (same with c-peptide levels).
In other words, insulin resistance leads to prediabetes, which leads to diabetes. It's thought that insulin resistance precedes diabetes by 10-20 years, but prediabetes can turn into diabetes in just one year. The person with a fasting glucose of 120 mg/dL isn't much better off than the person with a glucose of 126 mg/dL, seeing how they both had elevated insulin levels for at least one decade.
The problem is that many clinicians don't know what to do before a confirmed diagnosis. Many wouldn't know what to do with an elevated insulin level. Their plan would include lifestyle modifications such as weight loss, exercise, proper nutrition, and improved sleep. Perhaps they tell the patient they are at an increased risk for metabolic syndrome, so they print out a generic handout along with a two-minute copy-and-paste recommendation. Unfortunately, including this in the EMR doesn't truly help the patient.
To make matters worse, many do not know the nuances of personalizing any of these lifestyle recommendations, let alone have the time to implement them. It's discouraged. Here's an excerpt from a Mescape Article titled How PCPs are Penalized for Positive Outcomes from Lifestyle Change:
However, no current quality measures consider lifestyle interventions. In fact, some quality measures unintentionally penalize physicians for successfully treating or reversing disease through lifestyle behavior interventions while rewarding clinicians for meeting process measures — usually adherence to medication — regardless of whether health outcomes improved.
Rewarding medication adherence for the treatment of diseases in which lifestyle is a primary therapy (such as hypertension), combined with other healthcare constraints (lack of lifestyle education, time to spend with patients, and infrastructure support) incentivizes physicians to skip the conversation about lifestyle changes and go straight to medication prescription. Meanwhile, the clinician who takes the extra time to guide a patient toward lifestyle interventions that could treat their current disease and prevent future diseases — without side effects — is penalized.
Misaligned quality measures like these can stifle clinical judgment and risk reducing the practice of medicine to mindless box-checking. In many cases, patients are not even informed that lifestyle behavior change may be a treatment option (much less the first recommended option) for their conditions. This delivery of care is not person-centered and, in fact, may raise questions about the adequacy of informed treatment consent.
The system isn't set up to discuss the intricacies of health. We are trained to diagnose, prescribe, and manage risks. If there's nothing to diagnose, then there is nothing to prescribe and nothing to manage. Instead, we must wait until the criteria are met to intervene (even if it takes 20 years).
The crux of medicine revolves around a diagnosis, which is when a clinician is taught to intervene. But it's too late once a diagnosis exists. By this point, there has been dysfunction for decades, and it's challenging to change 20 years of behavior and dysfunction. Again, we know this intuitively and understand prevention is better than treatment. Therefore, the problem isn't necessarily knowledge. Like so many things, knowing how to do something is irrelevant if we don't do it.
Back to basics.
We must shift how we think about health and disease and use our tools differently. Albert Einstein is often credited with saying that insanity is doing the same thing repeatedly and expecting different results. Ideally, we want to intervene early and long before irreversible damage occurs. So, what does this look like? To explain, we must first go back to basics. Let's review the structural organization of the human body:
Subatomic particle: the parts inside an atom, which include protons, electrons, and neutrons.
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Atom: the smallest unit of an element (oxygen, hydrogen, etc).
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Molecule: two or more atoms form a molecule, i.e., two hydrogen atoms and one oxygen atom form a water molecule.
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Macromolecule: two or more molecules bond together to make a macromolecule, which includes carbohydrates, lipids, proteins, and nucleic acids.
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Organelles: structures that perform a specific function within the cell. They are comprised of several macromolecules bonded together. Organelles include the endoplasmic reticulum, Golgi apparatus, mitochondrion, nucleus, peroxisomes, and lysosomes.
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Cell: the smallest living organism capable of sustaining its own life. It consists of organelles inside a cytoplasm protected by a cell membrane. The cell is the fundamental unit of life.
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Tissue: a group of cells with similar structures that function together as a unit. There are four tissue types: epithelial, connective, muscle, and nervous.
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Organ: a collection of two or more tissues that work together to perform a specific function.
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Organ system: two or more organs working together to perform similar functions. There are 11 organ systems: skeletal, muscular, nervous, endocrine, cardiovascular, lymphatic/immune, respiratory, reproductive, digestive, urinary, and integumentary.
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Organism: We (humans) are considered organisms as we live, have an organized structure, and can carry out specific functions. We are a collection of the 11 organ systems that work in unison to keep us functioning.
This is the basis behind human physiology; everyone learns this during their basic science education. However, over the years, we have forgotten two fundamental principles that negatively affect how we practice medicine.
All organ systems are interconnected with the same common goal.
According to the Association of American Medical Colleges, there are 160 specialties in the United States. Originally, a physician was a generalist, and a specialist was an outlier. As we have gained a deeper understanding of medicine, more physicians have been drawn to specific problems. Beginning in 1880, specialization was deemed necessary around particular organ systems. This attempted to categorize people into groups so physicians could see more patients and as a strategy to conduct research as efficiently as possible.
In 1900, Jama wrote “The Dangers of Specialization.” In it, they write, “…we shall be able to understand that it is quite possible, by an excessive specialization, to hinder rather than favor medical progress and development.”
In theory, it makes sense to specialize. After all, there is so much to know that it would be impossible for one clinician to internalize every intricate and nuanced detail of the human body. This was my belief for as long as I can remember until I was met with this highly fragmented system. Our daughter was referred to the following specialists:
Geneticist
Neurometabolic/mitochondrial specialist
Hematologist
Rheumatologist
Immunologist
Cardiologist
Lipidologist
Ophthalmologist
Pediatrician
The list contains nine different specialties at various institutions. We know how busy clinicians are and how hard it is to do their day-to-day tasks. How can we expect nine different clinicians to coordinate care appropriately? It's impossible.
I caught many mistakes along the way only because I had the medical knowledge, the desire to keep learning, and the flexibility to be at every single appointment. I am in a unique and fortunate situation that has allowed me the luxury to be there every step of the way for my daughter. I am very well aware that 99% of parents can't do the things I have done for the last 2.5 years. Because of this, I know poor patient outcomes exist, many of which could have been prevented.
Although this is happening to my child, we all know this happens much more frequently to kids and adults than we think. Let's bring back those statistics.
According to the CDC, 60% of adults in the United States have at least one chronic disease, 40% have at least two or more chronic diseases, and 70% of all deaths are secondary to a chronic disease. It's estimated that 80% of chronic diseases and premature deaths could potentially be prevented. According to the National Council on Aging, nearly 95% of adults 60 and older have at least one chronic condition, while almost 80% have two or more. Finally, the CDC states that 40% of school-aged children in the United States are living with at least one chronic disease; that percentage jumps to 60% if we include behavioral mental health disorders.
As it stands, 60% of adults and 60% of school-aged children all have at least one chronic disease.
Every specialist is so focused on staying in their lane. Each specialist truly believes their specialty is the most important, and they forget that we have 11 interconnected organ systems. Each one is important in its own right, and disruption of one inevitably affects another (directly or indirectly). Every specialist I spoke to invariably said that “x” doesn't affect “y.” The more accurate sentence is that they don't know how “x” affects “y.” Not knowing something is not the same as it does not exist.
The more complex a system, the more likely it is to break. This is universally true across all industries.
The cell is the fundamental unit of life.
Interestingly, there isn't a clear consensus on the definition of a disease. Intuitively, we all know what it is; however, depending on the source, you'll find a different definition. This is partly why there is often debate regarding what should be classified as a disease, one of the more recent examples being obesity.
The World Health Organization doesn't even bother to define disease. Instead, they define health as a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. In other words, the lack of disease doesn't automatically equate to health, as many believe.
According to the WHO, the absence of disease doesn't define health, yet it's the only thing focused on during a clinician's training. The boards (regardless of profession) also emphasize disease recognition and management. This is the diagnostic process we are all too familiar with:
The patient history: gather clues to formulate a differential diagnosis
The physical exam: more information to help formulate a differential diagnosis
Differential diagnosis: a list of possible diseases that could be behind the patient's symptoms
Diagnostic testing: additional studies to help confirm a diagnosis
Treatment: this should be called management, as it's rare to cure anyone of any chronic condition
Don't get me wrong. Clinicians must know how to identify and manage the disease, as patients will always come in to see them at this stage. The problem is that we don't know how to intervene before the disease manifests. This is because before there is a disease, there are non-specific signs, symptoms, and biochemical abnormalities. Clinicians are uncomfortable with non-specific findings. So, instead, they tell the patient to follow up in a month, hoping that they worsen so that something is more specific instead of realizing there is already dysfunction that can be addressed.
But, even after the manifestation of a disease and intervention is initiated, many don't know what to do after the appropriate care is instituted. Treatment is typically a prescription to manage symptoms, improve labs, mitigate risk factors, or improve mortality. But what happens to the patient who feels unwell despite the clinician checking off all the appropriate boxes? From my experience, there are six common scenarios:
A referral is made to someone else.
The patient is told to wait to see if things resolve.
They go down the list and try second-line and third-line treatment options. If that doesn't work, they let the patient know they can explore other options that don't have the same efficacy; the irony is that the choices presented initially didn't work despite having the most evidence for their use.
They are told their labs look fine and there's nothing else to do.
They are told they've done all that can be done and there's nothing else to do.
They are told to consider seeing a therapist (perhaps it's all in their head).
I've seen these scenarios play out more times than I can count. So, patients are left to fend for themselves. They turn to blogs, social media, and friends for help. Many people turn to alternative solutions because medicine has already failed them. This comes with inherent risks, as they might seek help from someone who knows nothing about the human body.
Part of the problem is that clinicians were never taught to ask why until they reached the true root cause of the problem. Instead, we automatically assume a person manifests signs and symptoms because of the name we invented to recognize the constellation of signs and symptoms they present with.
Why is this patient presenting with fatigue, migraines, depressed mood, and insomnia? Oh, it's because he has major depression.
How do you know he has major depression? Because he has fatigue, migraines, depressed mood, and insomnia.
Do you see how that isn't helpful? It's about as useful as answering questions with a question.
Let's refer back to the structural organization of the human body. What step would the disease affect? If a patient has a disease (signs, symptoms, and biochemical abnormalities), we've reached a point where the organism is affected. If the organism is affected, then we know the following must be affected as well:
Organ system
Organs
Tissues
Cells
As you can see, the cell will always be the least common denominator, regardless of the manifestation. In its simplest form, all disease boils down to cellular dysfunction. This is empowering! Irrespective of the patient's complaint, we have only one goal: reestablish cellular homeostasis. The reverse is also true. If we have cellular homeostasis, we know we have healthy tissues, organs, organ systems, and a healthy organism.
We must optimize cellular homeostasis/allostasis to cure disease and create health.
Homeostasis: a self-regulating process (primarily using a negative feedback system) by which biological systems maintain stability.
Allostasis: defined as stability through change. It’s a physiological mechanism of regulation in which the human body anticipates and adjusts its energy use according to environmental demands.
Homeostasis waits for errors and then corrects them. Allostasis uses prior knowledge, both innate and learned, to prevent errors and minimize them.
The cell has specific nutritional requirements that need to be met to facilitate cellular homeostasis. If any of the following nutrients are missing, the result will be a cell with the inability to function appropriately:
Oxygen
Glucose
Fatty acids
Amino acids
Vitamins
Minerals
Important note: Many processes are involved in the absorption and utilization of each nutrient above. Any process that becomes dysfunctional will increase the requirement or limit utilization regardless of the patient’s nutritional intake.
The classic presentation
If you remember, specialties came about in 1880, long before we had a firm grasp of biochemistry. We grouped diseases based on presentations, which were often really late manifestations. The classic presentations we are forced to memorize aren't so classic anymore. A surprising example is celiac disease.
The classic presentation of celiac disease is malabsorption, diarrhea, and weight loss. However, this classic presentation only occurs in 27% of patients diagnosed. Non-classical celiac disease represents 52% of all cases, which could present with anemia, micronutrient deficiencies, elevated LFTs, neurological symptoms, dermatitis herpetiformis, poor weight gain, tooth enamel defects, or aphthous stomatitis. The other 21% of patients will be asymptomatic, even though they still have atrophy of the intestinal villi. The asymptomatic patient will eventually develop symptoms as a result of the intestinal villi destruction.
I do, however, call into question the asymptomatic patient. I've been around a lot of chronic diseases and have seen a discordance between what is on a progress note and what a patient experiences on a day-to-day basis. Often, the patient considers feelings of discomfort to be normal. Patients have no idea that others might not experience the same distressing symptoms. Alternatively, someone has lived with an ailment for so long that they have compensated for it. Compensation might temporarily relieve symptoms, but it is only helpful in the short term. Eventually, the body will be unable to compensate, and the problem will return to being worse than before. Lastly, the patient might not have enough time to address their symptoms in the 15 minutes allowed, or it's only after the visit is concluded that they remember.
Taking this into account, it's estimated that 73% of all patients with celiac disease have non-specific symptoms. Like other diseases, perhaps it's not as rare as we once thought. This results in misdiagnosis, and the patient will continue to eat gluten, further destroying their intestinal villi. Over time, they won't be able to absorb nutrients, leading to cellular dysfunction throughout the body, resulting in a poor quality of life and potentially decades of health problems that could have been prevented.
Redefining chronic disease
Hopefully, by now, we agree that the cell is at the heart of the health disease continuum. What then disrupts cellular homeostasis? Let's take a look at the four most common buckets of chronic disease in the United States:
Atherosclerotic disease: we don't have an identifiable etiology, but we know it's multifactorial.
Cancer: we don't have an identifiable etiology, but we know it's multifactorial.
Metabolic disease: we don't have an identifiable etiology, but we know it's multifactorial.
Neurodegenerative disease: we don't have an identifiable etiology, but we know it's multifactorial.
It's interesting how we've become so specialized but have yet to uncover why most people are sick. We know the epidemiology (sort of), pathophysiology (with limitations), risk factors, histological changes, and potential mechanisms, but not the etiology. This is partly because chronic disease isn't caused by one thing; it results from many things going wrong across multiple organ systems.
These factors can differ among people with the same disease. The same factors can also manifest as different diseases.
This is why etiologies can't be uncovered. There was a time when every scientist believed the human genome project would provide all the answers to disease. That was until the project revealed that 99% of our genes are noncoding. Monogenic disease accounts for only 6% of the population. Disease for the remaining 94% combines genetic predisposition and environmental factors. Again, we know this. The problem is most people want only one clear environmental factor to blame. However, it doesn't work that way and doesn't fit neatly into the boxes we created over a century ago. Our world is too complex, and human variability is too great, resulting in infinite etiological combinations that can't be identified with our current technology. That may change with a new model and more advances in the field. Regardless, we don't need to know every detail to restore homeostasis; we already know enough to make a difference.
The other problem we keep running into is illustrated nicely by this image:
Medicine is becoming increasingly fragmented, and clinicians must remember to zoom out and look at the whole picture. This is a classic example of losing the forest for the trees, albeit in a more sophisticated fashion.
Those doing research and trying to innovate should continue to specialize. But, the clinician helping patients needs to be much more of a generalist. When prescribed medication, it will invariably affect other organ systems (even if we don't know how to quantify those adverse events). Clinicians need to know about the entire organism they are treating. The disease is unaware of these arbitrary lines in the sand we've set for what we should know in our given specialty. If the goal is health for the organism, then the entire organism must be addressed. After all, every single chronic disease is never confined to one area. In every example, without fail, you will have multiple systems involved.
The underlying problem behind all chronic diseases is the same. The manifestation will differ depending on where the imbalance exists. If we were to rename the order of events, then what we classically call disease are signs and symptoms, and the actual disease is cellular dysfunction. The game now is to locate the imbalance and correct it. Everything that is upstream will self-correct or significantly improve if done correctly.
Instead of playing signs and symptoms whack-a-mole, let's focus on the biggest leverage point. If things still need to be addressed afterward, they can be addressed after we've solidified the patient's foundation. Of course, we must acknowledge that specific problems may be irreversible and largely dependent on the time it takes to address the cellular dysfunction. The longer we wait to address the imbalance, the bigger it will grow and the more it will transverse to other body parts.
Clinicians often like to give things time to unravel, but that strategy will inevitably lead to poorer outcomes. Fixing a leaking faucet is easier and cheaper than fixing a broken pipe. If you hold off on addressing the simple problem, the pipe could burst, potentially leading to irreversible damage. The body is no different.
Etiology of chronic disease
“For a long time, we have focused on the things that have caused the illness. The path from disease and chronic illness back to health is a different path.”
- Robert Naviaux, MD, PhD**
I want to take a second to introduce Dr. Robert K. Naviaux, founder and co-director of the Mitochondrial and Metabolic Disease Center (MMDC) at UCSD and is a Professor of Genetics in the departments of Medicine, Pediatrics, and Pathology at the UCSD School of Medicine, where he directs a core laboratory for metabolomics.
He is the co-founder and former president of the Mitochondrial Medicine Society (MMS) and the founding associate editor of the journal Mitochondrion.
Dr. Naviaux specializes in mitochondrial medicine and complex chronic disorders, discovered the cause of Alpers syndrome, and was part of the team that reported the first mitochondrial DNA mutation to cause genetic forms of autism.
Naviaux proposed the cell danger response (CDR) hypothesis in 2014, which helps explain the etiology behind all chronic diseases.
The cell danger response (CDR) is the response to a perceived threat (by the mitochondria) to protect the cells and host from harm. Common triggers include:
Chemical: heavy/trace metals, plasticizers (BPA, phthalates, etc), chemical flame retardants (BDE), or pesticides (chlorpyrifos, DDT, glyphosate, etc).
Physical: heat, salt, acid-base imbalance, or UV/ionizing radiation.
Microbial: viruses, bacteria, parasites, or fungi.
Trauma: particularly if this occurs during childhood.
A word from Dr. Naviaux regarding toxins:
Recent studies have established that mixtures of chemicals can have deleterious effects on metabolism even when no single chemical is present in concentrations defined as “toxic”. These findings have underscored a need for government agencies to revisit the guiding concepts in environmental toxicology called the “no observed adverse effect level” (NOAEL) and “lowest observed adverse effect level” (LOAEL), since low-level exposures to real-world mixtures of manmade chemicals can be toxic and produce chronic illness even at concentrations well below NOAEL.
Within every population, there are sensitive and resistant individuals, and the risk of harm is a probability, not a certainty, for any given person. Resistant individuals can remain healthy despite exposure at one particular time, but then become vulnerable in another season or after a predisposing event at another time. In sensitive children and adults, whose cell danger response has been primed by a perfect storm of previous chemical, microbial, physical, and/or psychological stresses, the same levels of chemical or biotoxin burden produce pathological and prolonged metabolic, epigenetic, and physiologic responses.
This hypersensitive response has two major effects: 1) it leads to disability and chronic illness, and 2) it interferes with the body’s natural efforts to heal.
When a threat is present, it will steal electrons from the cell and prevent them from going into the mitochondria for oxidative phosphorylation. The mitochondria will instantly sense this voltage drop and reduce their oxygen consumption. Because of this, the dissolved oxygen concentration increases, and the environment becomes more oxidized. This new environment prevents the formation of macromolecules (protein, carbohydrate, fatty acids, and nucleic acid), which ultimately blocks protein, DNA, and RNA synthesis. This also activates NFkB (proteins that control immune and inflammatory responses, developmental processes, cellular growth, and apoptosis). Simultaneously, the cell membrane will stiffen, reactive oxygen species will be produced, and various metabolic pathways will be altered, all in an attempt to protect the cell from further injury.
Between 2007 and 2008, The Environmental Working Group randomly sampled the umbilical cords of 10 babies born in Michigan, Florida, Massachusetts, California, and Wisconsin; they found up to 232 toxic chemicals in the umbilical cords. This is concerning as this alteration in children can have unintended consequences as the metabolic pathways may damage their neurodevelopment. Dr. Naviaux goes on to say:
If a child is born today with a burden of 300 manmade chemicals, in 25 years that child will add to their inherited burden by accumulating new toxic chemicals from their environment as they grow to reproductive maturity. As adults, they will then pass on a new sample of both their inherited and their newly-accumulated environmental chemicals to their children.
If a net increase of 50 environmental pollutants occurs in the umbilical cord blood with each generation, and is added to the current number of 300, the toxic chemicals passed on to our children will soon have more devastating effects on human health than any mutation in DNA, leading to escalating infertility rates, miscarriages, childhood and adult chronic disease.
The 2017 Lancet Commission on Pollution and Health states that pollution was responsible for 9 million deaths (16% of all deaths globally) annually.
Here's a snapshot summary depicting some of the altered metabolic pathways:
When a threat is present, metabolic pathways are shifted towards MTOR activation (growth metabolism): innate immunity, inflammation, and oxidizing conditions, as represented by the downward-facing arrows. Simultaneously, monomer (amino acids, fatty acids, monosaccharides, and nucleic acids) synthesis is prioritized, and polymer (protein, lipids, carbohydrates, and DNA) synthesis is deprioritized.
Conversely, when threats are absent, metabolic pathways are shifted towards MTOR inhibition (maintenance metabolism: reducing conditions and promoting healthy organism development, as represented by the upward-facing arrows). Simultaneously, the synthesis of polymers (protein, lipids, carbohydrates, and DNA) is prioritized.
If we revert our attention to the mitochondria, we'll notice that the cell defense response disrupts calcium homeostasis. The mitochondria will sound the alarm warning neighboring cells through purinergic signaling. Purinergic receptor nucleotides include ATP, ADP, UTP, and UDP; the mitochondria can use ATP as a neurotransmitter for cell-to-cell communication without it needing to be destroyed.
Eventually, the dysregulation of calcium leads to the spilling of mitochondrial proteins, which results in inflammation. When mitochondrial DNA leaks into the extracellular space, the innate immune system is activated via the TLR9 receptor.
Another key player is the gut microbiome. According to Dr. Naviaux, lab results are the collective metabolism of the host-microbiome system. Therefore, when the host is sick, the microbiome is also sick. Conversely, when the microbiome is sick, the host is also sick.
“The chronic activation of the CDR alters both the physical habitat of the distal bowel and the availability of resources in the form of dietary nutrients. For example, in children with autism spectrum disorders (ASD), the expression of intestinal disaccharidases is decreased so that the microbiota of the distal bowel receives a larger number of simple disaccharides like sucrose, lactose, and maltose (Williams et al., 2011).
In addition, the increase in oxidizing conditions associated with the CDR in cells lining the intestine leads to changes in the uptake, intracellular processing, and folding of the proline and glutamine-rich, processed gliadin 33-mer peptide (Oguma et al., 2007), and to an increase in gluten sensitivity (Jacobs, 2007).
These and other factors combine to alter the permeability and species composition in the gut. Among children with ASD, this commonly leads to dysbiosis and alternating bouts of constipation and diarrhea. It also leads to changes in behavior that are a result of communication abnormalities between the enteric nervous system (ENS) that monitors the health and function of the microbiome, and the central nervous system (CNS).
Restoring a sick microbiome is not as simple as adding back missing or underrepresented species. Both the physical habitat of the gut and the nutrient resources delivered must be durably changed in order to produce a durable change in the complex microbial ecosystem.”
- Dr. Naviaux
The Gut–Mitochondria–Brain Axis
Before we move forward to the healing cycle, I think it’s important to describe the interplay between the gut microbiome and mitochondria briefly.
According to the endosymbiotic theory, it’s believed that mitochondria were once bacteria that occupied residence inside larger bacteria to form a symbiotic relationship. This provided the mitochondria protection, and in return, the cell was provided with ATP and allowed to continue to evolve. Because of this, mitochondria have their DNA, which is always inherited from the mother. There are thousands of mitochondria inside a cell; the exact number varies depending on the ATP requirement of the cell.
The gut microbiome comprises bacteria, archaea, protozoa, viruses, and fungi. The vast majority of microbes are bacterial species. The microbiome comprises 100 trillion bacterial cells (only 37 trillion human cells), including up to 5,000 different species, with a total weight of approximately 4 lbs. The gut microbiome encodes over 3 million genes, producing thousands of metabolites, whereas the human genome consists of approximately 23,000 genes.
The numbers are important because they give context regarding these microbes' significance in chronic disease. However, this is all relatively new information, as the microbiome project was only completed in 2016.
The microbiome has multiple communication pathways, the most notable being the gut-brain axis, whereby the gut can send signals (GLP-1, ghrelin, CCK, GABA, serotonin, dopamine, and acetylcholine) to the brain via the vagus nerve.
It has also been recently discovered that gut microbes can communicate with their distant cousins, the mitochondria, throughout the body. Our gut microbes can produce short-chain fatty acids through fermentation, which can be used as energy and signaling molecules. For example, butyrate and propionate have been shown to activate PPARγ, which induces mitochondrial biogenesis and β-oxidation of fatty acids. Other metabolites used to communicate (positively and negatively) include secondary bile acids, indole-3-propionic acid (tryptophan metabolite produced exclusively from the gut), colanic acid (extracellular polysaccharide), and lipopolysaccharides (outer membrane components of gram-negative bacteria). SCFAs, trimethylamines, amino acid metabolites, and vitamins can be released directly into the bloodstream, affecting neuronal, endocrine, and immune pathways.
These microbes live inside our intestines, mostly the large intestine. A mucus layer (composed of mucin) helps facilitate the passage of food, assists in cell signaling pathways, and creates a physical barrier protecting us from pathogens, toxins, and other environmental chemicals. Just underneath the mucus layer sits the epithelium tissue (also a physical barrier), which is only one cell thick. Tight junctions hold this barrier together, which normally only allow certain molecules to pass (ions, solutes, and water). If the mucin is degraded and the tight junctions remain open, then substances that don't belong flow inside our body.
Just beneath this epithelial tissue lies the gut-associated lymphoid tissue (GALT), the largest lymphoid tissue in our body and home to 80% of our immune system. When foreign substances reach this tissue, they activate an immune response, which leads to one of the core threats/triggers discussed earlier.
As you can see, every system is related, and practicing medicine from an organ system point of view doesn’t consider all the recent advances we’ve made in understanding dysfunction and disease, let alone chronic disease.
It's important to remember that multiple factors mediate this entire process. After the cell danger response has been initiated, most inciting triggers will likely resolve. If any perceived threats continue to exist, they must be removed. However, this model doesn’t focus on uncovering one etiology. Instead, it looks for mediators that keep dysfunction going. Once the mediators have been removed, the body can move forward with the healing process.
The path to healing
Salugenesis is the multistep process of healing coordinated by mitochondrial and ATP signaling. Intracellular ATP drives cellular reactions, while extracellular ATP (released from pannexin channels) communicates (not energy) to alert nearby cells of danger. ATP will attach to receptors on the cell, which will be used to change gene expression.
The cell danger response has three stages, which must occur sequentially to achieve health. What makes each stage unique is the little-known fact that mitochondria change their phenotype depending on the stage they find themselves in. Recovery is an intrinsically active process that requires a lot of energy and resources.
“Any cell that has mitochondria that can’t change their function is either diseased or dead, or soon will be.”
If reinjury occurs during recovery, ATP is again released outside the cell. This slows the healing process, as the cell can't move to the next stage as long as extracellular ATP exists. If ATP continues to be released, the cell cannot use it intracellularly for healing, growth, and normal cell function. The cells on the receiving end will have oxidative phosphorylation blocked, resulting in fatigue; 19 purinergic receptors have now been identified.
If this reinjury process is repeated without resolution, this leads to what we know as aging.
If the extracellular ATP can be blocked, the cell is allowed to complete the healing cycle. If medication was used to do this, then at this point, the drug can be stopped as the therapeutic target no longer exists.
If you recall, the mitochondria will change accordingly as the cell moves through each phase. This newly discovered change calls into question the concept of mitochondrial dysfunction. It appears that it's only an apparent dysfunction because the mitochondria aren't behaving the way we think they are supposed to. The truth is, they are doing precisely what they are supposed to be doing. They aren't dysfunctional; we couldn't see the whole picture.
During health, our mitochondria have an M2 anti-inflammatory phenotype. When an injury occurs, the mitochondria change to an M1 phenotype that allows them to create an inflammatory response. Without the M1 phenotype, cells can't protect themselves because inflammation can't occur. After a few days, inflammation decreases, and the M1 phenotype becomes M0. The second stage is defined as the proliferation period and requires Warburg metabolism. The third stage is characterized by differentiation as new mitochondria with the M2 phenotype are created. Even though they have the M2 phenotype, they are fragile as they are still learning and adapting.
Once the healing cycle is completed, the cell stops releasing extracellular ATP. This signals the brainstem that the danger has resolved. The brainstem relays this message to other body parts through the vagal nerve to activate the cholinergic anti-inflammatory pathway.
If the healing cycle can’t be completed, the result is what we know as a chronic disease. The disease in question depends on various factors, i.e., the CDR stage in which healing was blocked, the patient’s underlying health status, and the location of cellular dysfunction. For example, if the cell is stuck during CDR1, chronic low-level inflammation will lead to upstream effects, resulting in many different disease possibilities. The figure below depicts a provisional classification of chronic disease created by Dr. Naviaux.
Facilitating the healing process
The healing process requires various components, such as proper nutrition, sleep, exercise, trauma resolution (big T or little T), and emotional, mental, and spiritual health. That is beyond the scope of this lecture. But we’ll continue to dive deeper in future lectures (the next lecture is coming soon). Due to unforeseen circumstances, I was forced to see there is more to health than we’ve been offering. Please realize others aren’t in my position, and they rely solely on you (the clinician) to help them create health.
We can do better.
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