Functional Medicine Research with Dr. Nikolas Hedberg

Zinc Functions Zinc is an essential trace element required by almost every biological process in the human body including growth and development, immune function, wound healing, protein and DNA synthesis, and cell division. It is used in over 300 enzymatic reactions, serves as an anti-inflammatory and an antioxidant, and is important for sight, hearing, and taste. The system-wide ubiquity of zinc increases the clinical importance of detecting and supporting a deficiency when present. Unfortunately, it is frequently underutilized in clinical practice. Gaining a deeper understanding of the many roles zinc plays in human health, learning the appropriate methods for assessing deficiency, reviewing which conditions may benefit from supplementation with zinc, along with supplementation guidelines and recommendations will increase the clinician’s confidence in the appropriate use of zinc with patients. Zinc Select Click here to learn more about the Hedberg Institute Membership. Causes of Zinc Deficiency The most common reasons for a zinc deficiency are increased losses of zinc, increased requirements for zinc, inadequate dietary intake, or reduced bioavailability/absorption of zinc. Increased losses can come from gastrointestinal diseases, surgery, trauma, oral contraceptives, and zinc lost in ejaculate with excessive sex. The requirement for zinc increases during periods of rapid growth, pregnancy, and lactation. Common examples of inadequate dietary intake include teenagers and college students as well as individuals following plant-based diets. Diets high in fiber are also rich in phytates which inhibit absorption. Dietary factors, such as the consumption of alcohol or following a vegetarian/vegan diet, can impair zinc absorption. Decreased absorption increases the risk for deficiency. Plant-based diets and diets high in seeds, legumes, and unprocessed whole grains contain phytates that bind with zinc, inhibiting its absorption. Soaking, sprouting, and/or fermenting can reduce the phytic acid content of these foods, increasing the bioavailability of zinc. It has been shown that the process of sour leavening to make sourdough bread reduced the phytate content by ~ 25% and increased the rate of zinc absorption by 30-50%. Other dietary factors that reduce the absorption rate include coffee, calcium in dairy products, increased fiber intake from fruits and vegetables, and a high fat diet (> 100g/day) in those with fat malabsorption issues. Deficiency can also be present in those with gastrointestinal issues that impair absorption such as Celiac disease, Crohn’s disease, or bypass surgery, and in those with hypochlorhydria (commonly seen with aging). Assessment of Zinc Status Laboratory Assessment A zinc deficiency is not always easy to recognize. It can manifest as a variety of symptoms and routine laboratory testing does not provide a reliable indicator of zinc status. Low plasma stores of zinc (~0.1%) cause the standard blood test for plasma zinc concentrations to lack sensitivity and specificity, making it unreliable as a marker of deficiency. Therefore, an assessment of zinc status and a diagnosis of deficiency is largely based on clinical findings. Clinical Zinc Assessment Zinc homeostasis is primarily regulated by the amount of zinc in the diet. Clinical evaluation should include a detailed review of the patient’s dietary eating patterns to determine if a deficiency is likely. The physical examination may reveal white spots on their fingernails and/or patches of dry skin. The patient history should be reviewed for associated conditions or medications known to cause impaired zinc absorption and a therapeutic trial of zinc may be recommended in those instances. A Zinc Taste Test provides a quick and inexpensive evaluation of zinc levels that can be conducted during the office visit. This test is not completely reliable due to the dependence on individual variances in self...

Berberine is an isoquinolone alkaloid that is bitter and bright golden yellow in color. It is derived mainly from the roots, stems and rhizomes of plants such as Coptis chinensis (Chinese golden thread), Hydrastis canadensis (goldenseal), Berberis aquifolium (Oregon grape), and Berberis vulgaris (barberry). It has been used for thousands of years in traditional Chinese and Ayurvedic medicine and is generally considered safe, though it should be avoided during pregnancy and lactation. Berberine Click here to learn more about the Hedberg Institute Membership. Gastrointestinal side effects may occur due to berberine's impact on bowel motility. These include abdominal pain, distention, nausea, vomiting, and constipation. Side effects appear to be dose dependent, with increased symptoms such as low blood pressure, dyspnea, and flu-like symptoms at higher doses. Berberine is commonly used as an antibacterial, antiviral, antimicrobial, antifungal, and antihyperlipidemic agent. The many therapeutic applications of berberine are due to its antioxidant and anti-inflammatory properties, making it one of the top supplements of choice in clinical practice. It has traditionally been used for gastrointestinal related issues as well as issues involving liver dysfunction, digestive complaints, blood sugar regulation, inflammation, and infectious diseases. While berberine has exhibited a bioavailability of

Background Information—Form and Function of B12 Vitamin B12 Form Cyanocobalamin has no known biochemical function. It must be converted to become active. It gets converted for use into hydroxocobalamin, methylcobalamin, or adenosylcobalamin. These three forms are equal in bioavailability.An exception to this is for the use of adenosylcobalamin in infants with a rare inborn error of synthesis.Methylcobalamin and adenosylcobalamin are coenzyme forms of B12.Hydroxocobalamin can be converted into the above two forms. Click here to learn more about the Hedberg Institute Membership. Vitamin B12 Function Vitamin B12 is used for DNA synthesis, homocysteine metabolism, S-adenosylmethionine, red blood cell formation, nervous system and immune system function.Vitamin B 12 is necessary for folate to be metabolized properly into Methionine and Succinyl-CoA. Low levels of B12 and increased levels of folate are associated with higher concentrations of methylmalonic acid (MMA) and total plasma homocysteine (HCY). Vitamin B12 Sources The average American diet contains adequate amounts of vitamins B12, ranging from 5-15 mcg/day. Meat, poultry, fish, eggs, and dairy, constitute the primary food sources. It is not found in most non-animal food sources. Individuals consuming a plant-based diet are at an increased risk of deficiency. Non-meat food sources such as chlorella, spirulina, nori, and fermented soy contain mostly B12 analogues which have no activity in humans. Fifty-one percent of those following a macrobiotic diet were found to be deficient.Vegan Diets 0.3-0.4 mcg/dayLacto-vegetarians 1.4 mcg/day Recommended Dietary Allowances (RDA)Males >14 years: 2.4 mcg/dayFemales >14 years: 2.4 mcg/dayPregnancy: 2.6 mcgLactation: 2.8 mcg Absorption of B12 Pepsin and hydrochloric acid (HCL) are necessary for cleaving B12 from protein in stomach.Individuals with low levels are at a greater risk of deficiency due to decreased break down for absorption.B12 supplements (crystalline B12) do not require HCL or pepsin to bind to intrinsic factor (IF).B12 supplements are absorbed normally in hypochlorhydria.Intrinsic factor (IF) is made in the stomach and necessary for carrying B12 from the stomach to intestines for absorption.Individuals with genetic SNPs impairing intrinsic factor (IF) production are also at a greater risk of deficiency and must rely on B12 injections, bypassing the need for IF.IF becomes fully saturated at 2 mcg of B12.Large doses can be absorbed through passive diffusion which doesn’t require IF. This accounts for 1-2% of absorption.1000 mcg/day can overcome loss of IF due to pernicious anemia.Pernicious anemia is an autoimmune disease characterized by the destruction of parietal cells which produce IF. Possible Causes of Vitamin B12 Deficiency Pernicious anemia—Auto antibodies against parietal cells and IFGastric disease or surgeryChronic atrophic gastritis—parietal cell death/autoimmuneUse of gastric acid inhibitors (antacids, histamine receptor 2 antagonists, proton pump inhibitors)Pancreatic disease or pancreatectomyOther intestinal diseases: parasitic infections, bacterial overgrowth, ileal resection, impaired B12/IF absorption.Medications, such as cholestyramine and metformin, that impair B12 absorption or metabolism.Limited/poor food sources/choices that result in general malnutrition. Examples include vegan or vegetarian diet.Chronic alcoholismInherited disorders involved in B12 trafficking and metabolismMiscellaneous: including HIV and nitrous oxide anesthesiaConditions that result in chronic diarrhea or malabsorption states, such as celiac disease and Crohn’s disease.Helicobacter pylori infection results in hypochlorhydria. Eradicating H Pylori can improve B12 levels.Long term psyllium supplementation (> 1 year)Genetic factors can affect absorption and transport. Individuals with genetically higher methylmalonic acid levels will require higher-than-normal B12 dose...

Many factors in our modern society increase the risk of magnesium deficiency, placing a vast number of individuals at risk of suboptimal levels. An individual’s magnesium level can become depleted from issues such as medication usage, chronic diseases, poor magnesium content in crops and soil, and the increased consumption of refined and processed foods. Magtein Magnesium L-Threonate Click here to learn more about the Hedberg Institute Membership. Magnesium L-threonate offers a cost effective, safe for long term use, and well tolerated form of magnesium that provides optimum levels. It has been shown to be the only form of magnesium capable of increasing magnesium levels in the brain and cerebrospinal fluid (CSF). This ability to cross the blood brain barrier (BBB) increases its efficacy for use in many chronic disease states, especially those associated with central nervous system (CNS) dysfunction. Conditions that respond to Magnesium L-threonate Magnesium L-Threonate and PainMagnesium is useful for treating chronic pain and inflammation that occurs due to the activation of the NMDA receptor during trauma. The NMDA receptor, which is normally not activated, becomes activated during traumatic physical or emotional events. During periods of excitotoxicity, calcium shuttles through the NMDA receptor and causes increased immune system responses (release of substance P, mast cells, immune cells, oxidative stress). Magnesium works to inhibit calcium influx through the NMDA receptor thereby decreasing oxidative stress as well as decreasing inflammation by blocking substance P. Blocking the NMDA receptor also serves to inhibit cortical spreading depression (CSD). Magnesium L-Threonate and MigraineMagnesium is also useful in treating migraine due to its ability to inhibit platelet activation. Platelet activation stimulates the release of serotonin which triggers spasming of blood vessels in the central nervous system (CNS) resulting in migraine. Magnesium inhibits calcitonin gene related peptide (CGRP) mediated vasodilation, another driver of migraine. Magnesium threonate is especially useful for the treatment of migraine as it is capable of crossing the blood brain barrier (BBB) and providing Mg2+ directly to the affected area. Magnesium L-Threonate and the EarMagnesium helps protect against hearing loss from noise as well as drug ototoxicity by decreasing the oxidative stress created by these stressors. Magnesium is also protective in sudden sensorineural hearing loss due to issues such as viral infections, vascular impairment, CNS disorders, inner ear abnormalities, or immune related mechanisms. Magnesium provides protection from hearing loss due to its ability to function as a Ca2+ antagonist, vasodilator, antioxidant, and a non-competitive NMDA antagonist.3 Magnesium threonate, with the ability to enter the CNS, is particularly useful in working with individuals with tinnitus. Protecting and Repairing the Hippocampus: Learning, Memory, and Emotion Alzheimer’s diseaseAlzheimer’s disease (AD) is associated with a magnesium deficiency in the serum or brain.7 Yu, Guan, Gu (2015) found that magnesium L-threonate enhanced the clearance of amyloid beta, the plaquing seen in AD. They demonstrated that magnesium L-threonate was able to slow the progression of AD.Magnesium threonate treatment was even effective at preventing synapse loss and memory decline when used in mice with end-stage AD. It has also demonstrated the ability to be neuroprotective against oxidative stress and hippocampal neuronal apoptosis. Chemotherapy-induced memory/emotional deficitsMagnesium L-threonate prevented oxaliplatin(OXA)-induced behavioral and synaptic changes in a 2020 study conducted using rats. This study showed that magnesium L-threonate prevented the OXA-induced upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and nuclear factor-kappaB (NF-кB).

The combination of hydrochloric acid, lipase, and pepsin combine to create the acidic gastric juices found in the stomach. These healthy stomach acid levels serve as a first line of defense for the gastrointestinal system, preventing infectious agents from reaching the intestines. A normal gastric pH is considered to be present with pH values >3, with values below 4 capable of killing bacterial invaders within 15 minutes. Gastric juices with a pH >3 mark the beginning stages of hypochlorhydria. As the pH increases above 4, there is an increased prevalence of bacterial overgrowth. Achlorhydria is defined as a pH >7. Betaine HCL Click here to learn more about the Hedberg Institute Membership. There are two main categories of hypochlorhydria: iatrogenic and acquired. Iatrogenic hypochlorhydria is the most common, resulting from the use of medications to reduce gastric acid secretions. Proton pump inhibitors (PPIs) are one of the top ten most prescribed drugs in the world, contributing to the rise in iatrogenic hypochlorhydria. Malnutrition is the leading cause of acquired hypochlorhydria. Individuals taking PPIs generally have a pH between 5-7. Individuals with hypochlorhydria are at an increased risk for infection and disease due to a loss of this protective barrier. Research conducted by Martinsen, Fossmark, and Waldum (2019) demonstrated that individuals with hypochlorhydria were at an increased risk of a variety of infections including bacterial, fungal, and parasitic infections. One study they reviewed reported a significant decrease in Shannon’s diversity of the GI microbiome and changes in 20% of the bacterial taxa in PPI users versus non-users. The increased use of PPIs makes it necessary to review current medications, both prescribed and over the counter, at each patient encounter. Nutritional status should also be evaluated utilizing blood labs, anthropometrics, diet diaries, food allergies/sensitivities, etc. Other useful factors in screening a patient for gastric hypoacidity include assessing gender, age, stress levels/eating behaviors, geographic origin/nationality, testing of stomach acid levels, and labs to rule out concurrent diseases such as Helicobacter pylori, chronic gastritis, parietal cell autoantibodies, hypothyroidism, etc. Keep in mind that there can be discrepancies between different testing methods and cutoff values depending on the labs used. Malnutrition can be the cause of or the result of hypochlorhydria. Malnutrition that leads to a deficiency in the nutrients needed to make HCL can cause hypochlorhydria. These include chloride, sodium, potassium, zinc, and iodine. Malnutrition can also develop as a result of hypochlorhydria. Decreased gastric acidity impairs nutrient absorption resulting in possible nutrient deficiencies for most of the essential vitamins and minerals including protein, iron, calcium, magnesium, zinc, vitamins A and E, copper, and all of the B vitamins. The presence of both malnutrition and hypochlorhydria increases the risk of enteric infections. There is also an increased prevalence of food allergies in individuals with reduced gastric acidity as they lose the ability to sufficiently denature proteins. With hypochlorhydria, larger protein peptides remain which can trigger an immune system response, resulting in allergic symptoms. Therefore, screening for hypochlorhydria should be conducted in individuals that suffer from malnutrition and/or food sensitivities/allergies. There is also an increased prevalence of food allergies in individuals with reduced gastric acidity as they lose the ability to sufficiently denature proteins. With hypochlorhydria, larger protein peptides remain which can trigger an immune system response, resulting in allergic symptoms. Therefore, screening for hypochlorhydria should be conducted in individuals that suffer from malnutrition and/or food sensitivities/allergies.

A new paper entitled, “Impaired Vagal Activity in Long-COVID-19 Patients” sheds light on the vagus nerve’s involvement in Long-COVID-19. COVID-19 is divided into three phases of infection: 1. “Acute COVID-19” (signs and symptoms of COVID-19 infection up to 4 weeks). 2. “Ongoing symptomatic COVID-19” (from 4 weeks up to 12 weeks). 3. “Post-COVID-19 syndrome” (signs and symptoms persist beyond 12 weeks). Click here to learn more about the Hedberg Institute Membership. Study Methods 30 Long-COVID-19 patients were compared to 20 control subjects who never had COVID-19. 21 patients were classified based on their experience while having COVID-19 as mild/moderate and 9 as severe/critical. 7 patients had no/negligible functional limitations, 6 had slight functional limitations, and 17 had moderate/severe functional limitations. No significant differences were found among study subjects and controls regarding gender, demographics, medical history, drug use, and vital signs. However, previous studies have shown that females are more affected by Long-COVID-19. Heart rate variability was measured through ECG. Heart rate variability parameters are controlled by the parasympathetic nervous system. The sympathetic nervous system promotes inflammation through catecholamines and beta-adrenergic stimulation in contrast to the parasympathetic nervous system which is anti-inflammatory. COVID-19 causes an imbalance between these two systems, thus driving inflammation and a procoagulative state. Study Findings Heart rate variability was found to be lower in the Long-COVID-19 patients. Left ventricular ejection fraction was lower in Long-COVID-19 patients. When SARS-CoV-2 comes into contact with the eye, it may reach the central nervous system via the trigeminal nerve. And when the virus contacts the nasal mucosa, it may reach the brain through the olfactory nerve. It may also travel to the central nervous system via the vagus nerve from the respiratory system, the heart, the digestive system, the kidneys, bladder, uterus, and testicles. This occurs through neuronal retrograde transport to the axonal terminal. SARS-CoV-2 has been detected in the vagus nerve, thus persistent damage to this nerve could explain impairment of the parasympathetic nervous system in Long-COVID-19 patients. SARS-CoV-2 can also invade the brain through a dysfunctional blood-brain barrier, which has been damaged by cytokine storm. SARS-CoV-2 binds to the ACE2 receptor found in the respiratory airway, lung, vascular endothelia, kidney cells, and small intestine. ACE2 receptors are also found in neurons and glia in the brainstem regions responsible for cardiovascular function and regulation. SARS-CoV-2 neuronal invasion drives epinephrine and norepinephrine from the adrenal gland known as the “catecholamine surge” which causes cardiovascular, lung, and brain injury. NT-proBNP levels were found to be increased in Long-COVID-19 patients, which reflects myocardial strain due to increased vascular pressure. This persistent myocardial strain may drive the dysautonomia, or it could be due to increased ischemia and inflammation. D-dimer can have prolonged elevation in Long-COVID-19 patients, which can lead to increased thromboembolic complications. Dysautonomia, neurotropsim, inflammation, and the persistence of a procoagulative state with an elevated myocardial strain may explain vagus nerve impairment in these patients. However, the authors state, “...it remains unclear whether dysautonomia associated with Long COVID-19 directly results from post-infectious immune-mediated processes or from the autonomic-virus pathway.” The authors call for research on evaluation of cholinergic nerve fiber damage in Long-COVID-19 patients to confirm impaired vagal activity. How to improve vagus nerve function? I have patients do a variety of exercises throughout the day such as singing, humming, gargling with water,