Monthly Miracles

by Michael Gerber, MD, HMD

Nevada Homeopathic Integrative Medical Association Conference: The Brain Trust

Part 3

The October 2011 Nevada Homeopathic Integrative Medical Association (NHIMA) annual conference produced an incredible number of revelations in health medicine. This brain trust of treasured, integrative physicians and innovative scientists has profoundly enhanced my view of medicine on many levels. The following reviews of that conference will hit the high points of these great presentations. The whole conference is available on DVD for $145. Contact info@nevadahomeopathy.org or Tiffany at 775-742-4695.

Frank Shallenberger, MD, HMD, ABAAM

Cancer is a Mitochondrial Deficiency Disease

Frank Shallenberger (www.antiagingmedicine.com) is a great pioneer in integrative medicine. He is author of three books and many important articles and presentations. Ozone therapy is one of his primary therapeutic interests, and his book The Principles and Applications of Ozone Therapy is available at Amazon.com. He welcomes new members to his American Academy of Ozonotherapy (www.aaot.us), which is dedicated to establishing standards for ozonotherapy, educating health professionals and the public of the many uses of ozone in medicine and promoting research in the field.

Otto Warburg

Otto Warburg (1883–1970) was a German physiologist and medical doctor. He won the 1931 Nobel Prize in Physiology/Medicine because of his paper “The Metabolism of Tumours.” Warburg proved that the fundamental difference between normal and cancerous cells was that normal cells had effective mitochondrial function, whereas cancer cells had deficient function. He also wrote “The Prime Cause and Prevention of Cancer,” which he presented at a lecture at the meeting of the Nobel laureates on June 30, 1966 at Lindau, Lake Constance, Germany. In this speech, Warburg presented evidence proving that the primary cause of cancer is decreased mitochondrial function. The decrease in mitochondrial function causes increased free radicals to form, which mutate the nuclear proto-oncogenes (initiation) and drive nuclear replication (promotion), resulting in cancer.

“Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth: Otto Warburg Revisited.”¹ Researchers postulated that cancer cells exhibit multiple alterations in mitochondrial content, structure, function, and activity. They overexpressed the protein frataxin in several colon cancer cell lines, causing them to have increased mitochondrial function. Consistent with Warburg’s hypothesis these cells had: (a) decreased growth rates and increased doubling times, (b) inhibited colony formation capacity, (c) a reduced capacity for tumor formation when injected into nude mice. “These results support the view that an increase in oxidative metabolism may inhibit cancer growth in mammals.”

“Alteration of The Bioenergetic Phenotype of Mitochondria Is a Hallmark of Breast, Gastric, Lung and Oesophageal Cancer.”² Mitochondrial function is depressed in all cancers studied so far including breast cancer. “Pyruvate Utilization, Phosphocholine and Adenosine Triphosphate (ATP) Are Markers of Human Breast Tumor Progression.”³ This study compared breast cancer cells with normal breast cells and found a 30% decrease in ATP levels and an 83% decrease in phosphocreatine levels “suggests impaired mitochondrial metabolism in the breast carcinoma cell lines.” “These results demonstrate that diminished mitochondrial energy generation may be quantitatively related to the progression state of human breast cancer cells.” That is, malignancy potential correlates with mitochondrial dysfunction.

Mitochondrial Function Can Be Determined Using Pulmonary Gas Analysis

ATP production is directly correlated with O2 utilization. Pyruvate dehydrogenase (PDH) activity is directly correlated with O2 to CO2 ratios. Anaerobic metabolism is directly correlated with O2 to CO2 conversion. After testing, Dr. Shallenberger’s patients had a 46 % decreased mitochondrial function. Causation of mitochondrial function include decreased oxygen intake-decreased FVC, decreased circulation, decreased fat metabolism caused by hormonal deficiencies, inadequate aerobic fitness, sleep deprivation, and excessive carbohydrate intake, B vitamin deficiency, stress (especially adrenal insufficiency) and environmental toxicity. Treating mitochondrial deficiency involves detoxification, diet, chelation therapy to remove heavy metals, properly done aerobic exercise, hormonal replacement, supplements, stress management and oxidation therapy. To learn more about Dr. Shallenberger’s mitochondrial functional analysis visit www.antiagingmedicine.com and click on “Bio-Energy Testing.”

Treating Diabetes and Cancer with Dichloroacetate (DCA)

Dichloroacetate inhibits PDK (pyruvate dehydrogenase kinase), which causes normalization of ATP production. Why do cancer cells have high aerobic glycolysis? Carcinogenesis begins in a hypoxic environment. This forces the cells to adapt to and rely on glycolysis by upregulating PDK. This downregulates mitochondrial functions and hence apoptosis and creates a heavily acidic microenvironment which facilitates metastases by breaking down the extracellular matrix

DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Mitochondrial function in cancer cells is upregulated by DCA: increases H2O2, decreases lactate, increases NADH, and increases intracellular pH. DCA crosses the blood–brain barrier and can be blocked by catalase. DCA inhibits neuroblastoma (NB) growth by specifically acting against malignant undifferentiated cells.⁴ This effect is selectively directed to very malignant neuroblastoma cells, whereas the more differentiated/less malignant NB cells are refractory to DCA treatment. Additional studies suggest apoptosis induction by DCA in glioblastoma (and glioblastoma stem cells), endometrial, prostate, breast and non-small cell lung cancers.^5–8

Charles Price, MD

From the Bench to the Consulting Room: Basic Science Informing Clinical Practice in the Treatment of Depression

The Inflammatory Hypothesis of Depression

Dr. Charles Price is a distinguished psychiatrist in Nevada. He has been a professor of psychiatry at the University of Nevada School of Medicine and is the current president of the Nevada Psychiatric Association. His remarkable curriculum vitae includes being a lead researcher in over 18 clinical drug trials supported by the pharmaceutical industry; notes presentations and appointments in national and international psychiatry governance and teaching, including Cuba, China, and Sweden; and he has held many posts in the American Psychiatric Association. Although not a familiar figure in integrative medicine, his willingness to bridge the gap with standard allopathic practice and study the physiological importance of anti inflammatory markers and endocrine relationships as they relate to depression and psychiatric drugs is an important service to our larger medical community.

Stress

Dr. Price reviews the complex chemical language of stressors at all levels of human physiology, including neurotransmitters and hormones as well as interleukins, interferons, TNF-a and chemokines. For example, epinephrine is a critical immune regulator that decreases monocytes, B and T cells, and NK cells, as well as inhibiting pro-inflammatory IL-1, IL-6, TNF-a and increasing secretion of anti-inflammatory IL-10.⁹ The parasympathetic nervous system regulates immune responses via release of acetylcholine from the motor vagus nerve and inhibits pro-inflammatory cytokine release.¹⁰ Neurotransmitters not only function in the nervous system, but also critically regulate immune responses.

When stress becomes chronic, the body burns resources faster than it can replenish them. Chronic immune activation and its neurobehavioral effects can lead to decompensation and clinical depression. Serotonin metabolism can be dysregulated by IFNy and TNF-a, activating microglia and promoting NMDA receptor activity giving excitotoxicity, memory effects, and neurodegeneration.¹¹ Inflammation and diets low in tryptophan limit 5-HT synthesis; stress accelerates 5-HT metabolism. These factors can lead to 5-HT deficiency and ultimately symptoms associated with low serotonin.

Treatments Targeting Inflammation in Depression

“The importance of the inflammatory hypothesis of depression lies in raising the possibility that psychotropic drugs that have a central anti-inflammatory action might provide a new generation of antidepressants.”¹² Such treatments include TNF antagonists such as etanercept, infliximab, anti-inflammatory cytokines, IL-10, insulin-like growth factor, glutamate modulators, risuzole (used in ALS), COX inhibitors/NSAIDS (celecoxib, aspirin, ibuprofen, naproxen), traditional antidepressants that depress IL-6 such as fluoxetine, and other antidepressants that decrease INF-gamma/IL-10 ratio (imipramine, clomipramine, venlafaxine, fluoxetine, sertraline, and trazadone).

Individualizing treatments for depression including dietary and behavioral modification such as meditation/tai chi, mindfulness-based cognitive therapy, compassion meditation, short-term medication, and various yoga techniques should always be encouraged.

Future Directions

“Given the mounting data that the immune system may contribute both to the development of neuropsychiatric disease as well as the maintenance of neuronal integrity, there is increasing need to (1) test neuropharmacologic strategies that target the nervous system to treat neuropsychiatric disorders such as depression and (2) develop better biomarkers to measure the relative status of the immunologic response. There is a clear and pressing need for faster, robust and well tolerated therapy/therapies. Thinking is rapidly changing and evolving-combination strategies from treatment initiation may be the new frontier for patients who need greater efficacy than antidepressant monotherapy. Personalized medicine may be needed to address genetic differences in depressed individuals to achieve and maintain remission.”

Bridget R. Briggs, MD

Assessing and Addressing Inflammation as an Underlying Factor in Chronic Disease

Dr. Briggs (Murrieta, California) brings a fascinating personal and professional history to her presentation. The family-practice physician and mother of five was stimulated to learn about functional medicine when her 4-year-old developed brain cancer in 2005. She is a brilliant, rising star in functional/orthomolecular/integrative/complementary medicine, with a terrific accumulation of powerful data to support her well-rounded view of medical evaluation and treatment of those patients whom we all see every day. Graduating from UC San Diego School of Medicine in 1993, she completed her family practice residency in 2001 and has been a featured speaker for numerous pharmaceutical companies and lately nutraceutical and advanced laboratory evaluation companies. She was a featured speaker for the American Academy of Family Practice, “What is Functional Medicine,” in San Diego summer 2011. Her presentation and extended presentations are available from Dr. Briggs and are primers for any physician who seeks a firm foundation and understanding of the state of the art in integrative medical practice.

The Neuro-Endo-Immune (NEI) System

Stress is registered in our body in many ways and influences the NEI system, and health issues can be pinpointed by assessing imbalances in this system. Societal stresses such as job demands, information overload, multitasking, social pressure, strained relationships, breakdown in social structure, diet, processed foods, environmental insults, and overmedication all contribute to our modern stress. Pathogens (bacterial, viral, fungal, parasitic), metals, and other toxins and foods can all lead to morbidity via direct effects and indirectly by causing chronic inflammation. By measuring important biomarkers of health, we can define which systems are causing health issues. The following biomarkers are key to elucidating these dysbalances.

• neurotransmitter analysis.

• endocrine/adrenal analysis.

• cytokine analysis of immune function.

• heavy metal analysis: allergen vs. toxic exposure.

• food intolerance/gut barrier status

• advanced stool analysis

• serum putative markers of detoxification.

• single nucleotide polymorphisms

Neurotransmitter analysis can reveal neurological imbalances and objectively establishes the need for intervention with missing or balancing amino acid precursors. Assessing hormones levels can reveal imbalances in the HPA/thyroid/gonadal axes. WBC cytokines reveal immune imbalances. Measuring reactivity to specific viral, bacteria, fungi and heavy metals can also reveal origins of NEI imbalance.

Metal hypersensitivity can be measured by a MELISA (memory lymphocyte immune system analysis) study, which shows allergies to metals, especially dental materials, which can cause chronic inflammation and diseases. Toxic metal exposure can be measured by serum analysis, heavy metal 24-hour urine measurement (especially after challenge testing with chelators such as EDTA, DMSA, DMPS, and others as well as hair analysis which is inexpensive, nontoxic, and reliable [Dr. Gerber]).

Food sensitivities are a common cause of inflammation (gluten, sugar, cow dairy) and imply abnormal intestinal permeability. Advanced stool analysis can reveal unknown infections that can be easily treated and show commensal bacterial in the GI tract as well as inflammation (salivary IgA, lysozyme). Single nucleotide polymorphisms found in genetic analysis studies show common glitches in DNA such as MTHFR, methylene-tetrahydrofolate reductase (30% to 40% of all patients who don’t methylate properly), COMT, catechol-O-methyl-transferase (can’t break down dopamine, norepinephrine, and epinephrine and are chronically anxious with panic attacks), cytochrome P450 various SNPs, HFE, hemochromatosis SNP, HLA, DQ2/DQ8, celiac disease, and autoimmunity markers. She also reminds us that hemoglobin A1c more than 5.5%, D3 levels less than 30 ng/ml, urinary microalbumin over 30 mg in 24 hr. GGT over 40 which must be carefully monitored in all patient care. Uric acid over 8 mg/dl, homocysteine over 11, C-reactive protein over .7 mg/L, magnesium less than 2 meq/dl, and ANA titer over 1:125 as well as many other usual biomarkers for toxicity are also important to evaluate.

Urinary neurotransmitter testing has been shown to be a consistent evaluation device. Urinary norepinephrine correlates with severity of depression and anxiety. Serotonin deficiency is correlated with major depressive disorder. Sympathetic involvement is shown in depression, anxiety, and sleep disorders. Glutamate is involved in depression and insomnia and is correlated with elevations in urinary catecholamines. We all should recognize excitatory/inhibitory neurotransmitters. Inhibitory neurotransmitters include serotonin, glycine, taurine, and GABA and the excitatory neurotransmitters are epinephrine, norepinephrine, dopamine, glutamate, PEA, and histamine.

Dr. Briggs has marvelous diagrams to help understand the various white blood cell cytokines and how they fit into the Th1/Th2/Th17 and Treg immune systems (Plates 1 and 2). After the body becomes sensitized to new antigens, antibodies are produced and the patient’s symptoms can become more severe and cause neuropsychiatric disorders, autoimmune disease, and chronic inflammatory disorders.

Metals

Metals induce free radical pathology and mitochondrial damage, serve as “mitochans” (i.e., mitochondrial toxins), and uncouple bioenergetics and ATP production.¹³ Metals including lead, cadmium, mercury, nickel, platinum, palladium, tin and arsenic induce oxidative stress.¹⁴ Mercury has been demonstrated to increase antinuclear antibodies and induce autoimmune disease. The clinical consequences of mercury toxicity include hypertension, CHF, MI, carotid obstruction, CVA, and renal failure.¹⁵

The Gut: ‘Inner Tube of Life’¹⁶

The enteric nervous system contains between 200 and 600 million neurons, far more than any other peripheral organ; is critical for balancing the NEI system; and is the largest immune organ, with 70% of the body’s immune system.¹⁷ The intestinal tract also harbors an extensive endocrine signaling system and is the largest endocrine system of the body, with over 30 hormones acting as acute metabolic modulators, local growth factors, and neuromodulators. The best studied are gastrin, CCK (cholecystokinin) and secretin. Many gastrointestinal functions are under dual neuronal and endocrine control. Gut-associated lymphoid tissue (GALT) are represented by Peyer’s patches (think about beefing up Peyer’s patches with Rebas, from Pleo Sanum – MG), tonsils, mesenteric lymph nodes, and appendix.

Intestinal barrier dysfunction (IBDF) has been linked to GI and non-GI conditions including food sensitivities and allergies. All aspects of health are compromised by persistent IBDF permeability and should be supported with soluble fiber, insoluble fiber, demulcents, antioxidants, and probiotics to reduce swelling, increase secretory IgA and inhibit yeast overgrowth. Dr. Briggs particularly mentions Saccharomyces boulardii as the lawnmower of the intestines, the yeast that kills yeast.

Remember the Liver

Dr. Briggs gave a great review of phase 1 and 2 liver detoxification and the major job it does in detoxing (she calls it the “car wash” – soap up and rinse). Remember that the liver removes pollutants, insecticides, pesticides, metabolic end products, food additives, bacterial toxins, drugs, and alcohol. Glutathione is the principle antioxidant in our bodies and needs selenium and riboflavin to help it work.

Biocides

Glyphosate (Roundup) damages DNA in immune cells due to mitochondrial inhibition.¹⁸ Bisphenol A markedly increases breast milk duct density in mice and depletes glutathione concentrations as well as increasing apoptosis.¹⁹

Methylcobalamin

Methylcobalamin is used in the treatment of peripheral neuropathy and diabetic neuropathy, and as a preliminary treatment for amyotrophic lateral sclerosis. It plays a huge role in biomethylation, especially with individuals with one or both of the MTHFR SNPs and is responsible for the biomethylation of certain heavy metals; for example, the highly toxic methylmercury. Methylcobalamin has been studied in conjunction with sleep-wake rhythm disorders, where it appears to yield benefits.²⁰ Supplementation with megadoses of methylcobalamin and 5 methyl folic acid has been advocated to protect the cognitive function of patients suffering chronic fatigue, stroke, depression, Alzheimer’s, and other neurological diseases.

Dr. Briggs also brings many exemplary case studies that illustrate her approach and amplify the efficacy of these therapies. Watch her tapes and attend her lectures to hone your understanding of our average and also very difficult patients. I highly advise readers to study all of these NHIMA DVDs to round out your knowledge of these great presentations by the Brain Trust physicians.

Notes

1. Schulz TJ, Thierbach R, et al. J Biol Chem. 2006 Jan 13; 281(2):977–981. Epub 2005 Nov 1.

2. Isidoro A, Martinez M, Fernandes PL, et al. Biochem J. 2004 Feb 15;378(Pt 1):17–20.

3. Singer S, Souza K, Thilly WG. Cancer Res. 1995 Nov 15;55(22):5140–5145.

4. Vella S, Conti M, Tasso R, Cancedda R, Pagana A. Int J Cancer. 2011 May 9.

5. Michelakis ED, Sutendra G, Dromparis P, et al. Sci Transl Med. 12 May 2010;2(31):31–34.

6. Ko L, Allalunis-Turner J. J Clin Oncol. 2009;27.

7. Sun RC, Fadiaet M, et al. Breast Cancer Res Treat. 2010 Feb;120(1):253–260. Epub 2009 Jun 19.

8. Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I. Gynecol Oncol. 2008 Jun;109(3):394–402.

9. Oberbeck R. Neuroimmunomodulation. 2004;11(4):214–223.

10. Stemberg EM. Nat Rev. 2006;6:318–328.

11. Adapted from Dantzer R et al. Nat Rev Neurosci. 2008;9(1):46–57.

12. Leonard BE. Curr Immunol Rev. 2010;6(3):205–212.

13. Recent Pat Anticancer Drug Discov. 2006;1:327–346.

14. Curr Med Chem. 2005;12:1161–1208.

15. Houston MC. Altern Ther Health Med. 2007;13(2): 128–133.

16. Science. 25 March 2005;307

17. Faragasan S, Honjo T. Nat Rev Immunol. Jan 2003;3:63–72.

18. Mladinic, Berend, Zeljezic. Environ Mol Mutagen. 2009;50:800–807.

19. Groff T. Bisphenol A: invisible pollution. Curr Opin Pediatr. 2010;22:524–529.

20. Psychiatry Clin Neurosci. 1999 Apr:53 (2):211–213.