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Targeting Mitochondrial Support for Combating Fatigue

Debby Hamilton, MD, MPH


Fatigue is one of the most common concerns among patients. Causes for long term fatigue are vast and frequently accompany most chronic diseases. One cause of fatigue that is common in these diseases is mitochondrial dysfunction. With chronic diseases ranging from tick borne infections to neurodegenerative diseases, there is ongoing inflammation and oxidative stress. Both of these pathologic processes damage the mitochondrial membrane leading to a cascade of events that progress to mitochondrial dysfunction. By looking at repairing the cell membrane and supplementing key nutrients, mitochondrial function can be improved. Research on ATP360® has shown improvement in fatigue markers with supplementing phospholipids for cell membrane support along with key nutrients. Improvement in mitochondrial biogenesis and membrane potential correlated with the improvement in fatigue, pain and inflammatory cytokines. The improvement in fatigue was accompanied by improvement in other common symptoms experienced by chronically ill patients such as sleep difficulties and decreased mental functioning.

Learning Outcomes

  • Discuss common causes of mitochondrial dysfunction including inflammation and oxidative stress and why this causes fatigue in many chronic illnesses
  • Learn about the different nutrients needed to support the function of the mitochondria
  • Discuss research on the supplement ATP360 that shows an improvement in fatigue, mental functioning, and sleep with nutritional support of the mitochondria


Where CFS, viruses and TBDs Intersect

Eric Gordon, MD


CFS is usually precipitated by a stressful event. Most of the focus has been on viral illness such as EBV and HH6 and 7 as well as CMV. We will review the early work by Cheney and others and the documented treatment responses obtained by Dr. William Lerner and later the work of Jose Montoya and the Stanford group. We will present Dr. Naviaux's CFS and metabolomics paper and use it as a jumping off point to discuss TBD as a precipitator of CFS. We will also discuss Cell Danger Response in light of Dr. Prusty and Naviaux's 2020 paper which showed that there was a serum factor in CFS blood that prevented normal cells in cell culture from getting infected by HSV-1 and influenza. We will end with our clinical opinion on differentiating CFS from Chronic TBD

Learning Outcomes

  • Discuss the possible triggering mechanisms of viral infection and CFS
  • Show the data behind the various viral induction theories and the effects of antiviral therapy
  • Discuss observations and data showing TBDs triggering CFS and the CFS persistence after TBDs eradicated
  • Discuss the Prusty /Naviaux 2020 paper and its relevance to understanding persistent symptoms through the perspective of the Cell Danger Response and using this perspective to guide therapeutic interventions


Factors that Cause Hypothyroidism That is not Detected by Thyroid Function Tests

Kent Holtorf, MD


The majority of patients with a tick-borne illness will have low cellular thyroid function that is not detected by standard thyroid tests. These low intracellular T3 levels are often a major contributing cause to the severe fatigue experienced by these patients. With an understanding of the pathophysiology occurring in these patients, practitioners will be able to recognize and treat such patients, which often results in significant improvement in fatigue, not uncommonly dramatically.

In Lyme and other tick-borne illnesses, there is a vicious cycle that occurs of immune dysfunction, mitochondrial malfunction (consistent with the cell danger response), and hypercoagulation that leads to autoimmunity (often not detected by standard testing), excessive inflammation, secondary and tertiary hypothyroidism, decreased T4 to T3 conversion, increased reverse T3 levels, thyroid resistance, and defective thyroid hormone transport into peripheral cells. In contrast, the transport of T4 and T3 into the hypothalamus and pituitary and T4 to T3 conversion is increased in the hypothalamus and pituitary, opposite to what is happening in the periphery. This results in the suppression of the TSH and subsequent central hypothyroidism.

The decreased transport of T4 and T3 into the cells in the periphery serves to artificially raise serum thyroid levels, masking the fact that these patients are suffering from significantly low cellular thyroid activity throughout the body, except in the hypothalamus and pituitary. These patients often present with a low normal TSH, a high normal or normal T4, and a low normal or normal free T3 level, leaving the typical doctor or endocrinologist with the impression that these patients are normal or even borderline high thyroid. However, through a review of the literature, I will show this is not the case and that such patients can benefit from treatment.

These patients can significantly benefit from not only proper thyroid replacement but with therapies that modulate the immune system, boost mitochondrial function, and treat the hypercoagulability. It can often make the difference between treatment success and failure in these patients.

Learning Outcomes

  • To understand normal thyroid physiology and mechanisms of adaptive and maladaptive physiology
  • To understand the limitations of TSH and other thyroid function tests, especially with chronic illness
  • To understand the steps required to maintain euthyroidism and what can cause pathology and dysfunction in each step
  • To understand the importance of local control of cellular thyroid levels (deiodinase activity alterations)
  • To understand the importance of central thyroid dysfunction (different causes discussed in each lecture)
  • To understand how patients can suffer from “tissue hypothyroidism” but have thyroid function tests (TFTs) in the normal range (normal TSH and serum thyroid levels)
  • To understand how toxins and nutrient deficiencies can affect cellular thyroid function
  • To understand different causes of central hypothyroidism and thyroid resistance
  • To understand how chronic illness, stress, obesity, inflammation, depression, and other conditions, resulting in reduced thyroid hormone transport (THT) into peripheral cells while thyroid transport into the pituitary cells increases
  • This results in peripheral cellular hypothyroidism with a normal or low normal TSH because the pituitary maintains or increases the uptake of thyroid.
  • To understand how THT dysfunction is much more common than autoimmune thyroid disease (Hashi) and is the most common cause of symptoms of hypothyroidism
  • To understand how autoimmune thyroid disorders are more complex than once thought and can cause a wide-range of HPT axis and cellular dysfunction
  • To understand how to diagnose and treat hypercoagulability and understand how it can cause thyroid resistance.
  • To understand the clinical signs and symptoms of hypothyroidism
  • To understand what further tests can be done to aid in the diagnosis of hypothyroidism
  • To understand the association between low-normal thyroid levels and disease
  • To understand the risks and benefits of thyroid replacement in a wide range of conditions
  • To understand the differences in thyroid preparations, including T4, T4/T3, and straight T3
  • To understand the actions and potential benefits of T2
  • To understand when to consider non-standard thyroid preparations, such as T4/T3 and T3 products vs. standard T4 replacement.
  • To understand the potential side-effects and risks involved with such treatments and how to properly monitor patients on such treatments


Monitoring patients during chronic fatigue – An Immune System perspective

Felix Scholz, PhD


Chronic fatigue is a challenging disease for patients to manage. Underlying conditions can be tricky to identify and once Identified even harder to assess or monitor. We know that viruses from the Herpes family such as HSV-1, EBV, CMV and HHV6 are found in a high frequency of the population. It is known that mitochondrial cell danger response is involved in chronic fatigue. It is suspected that reactivation of viruses from the herpes family such as HHV6 can be drivers of that cell danger response. Recently published data show that serum from Chronic fatigue patients with viral reactivation induced the mitochondrial cell danger response in cell culture experiments indicating that a factor from the virus or the immune response to the virus may trigger that response. This highlights the need for tools that can help understanding chronic controlled and reactivated herpes family viral infections. Laboratory test have their own technical and physiological limitations. Most tests are useful to identify or narrow down the underlying conditions in patients, but most are not able to provide information beyond that aspect. Monitoring the immune responses can provide useful additional information. Antigen specific T-cell subsets are the ideal candidate to check if a patient is in a chronic controlled stage or in a re-activation phase. This is possible with specific antigens that are expressed on the surface of the viral particles in latent and lytic stages. The presence of antigen specific T-Cells subsets and their frequency helps to better understand the stage of viral infections chronic controlled or reactivated. Furthermore, it enables us to check for improvement post treatment.

Learning Outcomes

  • Understanding the relationship of herpes virus family and chronic fatigue
  • Understanding the relationship between viral load and antigen specific T-cell subsets and their frequencies
  • How to use antigen specific T-cell subsets to understand what stage chronic infections of herpes viruses are in patients


Chronic Fatigue in Lyme Disease, a Multisystem Complex

Samuel M. Shor, MD


Fatigue is a very common complaint with a number of meanings. Fatigue can relate to limits in endurance, sleepiness, as well as cognitive and emotional limitations. If the fatigue lasts for more than 6 months, it fulfills the definition of “chronic.” The Center for Disease Control (CDC) has established specific criteria for the diagnosis of CFS. This is characterized by a persistent or relapsing debilitating fatigue for at least 6 months in the absence of a medical diagnosis that would otherwise explain the clinical presentation. CFS represents a heterogeneous group of patients that manifest symptom complexes with varying degrees of fatigue, limited exertional reserve and cognitive dysfunction. [1] In fact, in our retrospective analysis of patients fulfilling the International Case Definition of CFS, we provide clinical evidence that the majority of the cohort studies in fact had sero-negative chronic Lyme disease [2] or associated tick-borne infection. [3]

We will explore multiple contributing factors for fatigue in Lyme disease. This would include fractured nonrestorative sleep, endocrinopathies and mood disorders. In addition, we will discuss new concepts such as Biotoxin Illness [4] and Mast Cell activation Syndrome [5] that often contribute to this morbidity.

Learning Outcomes

  • Identify 3 systems that can contribute to chronic fatigue in Lyme disease
  • Describe 3 types of conditions that can contribute to chronic fatigue in Lyme disease
  • Identify 3 diagnosis for which there is a significant overlap in clinical presentations