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Human herpesvirus 6 (HHV6) is part of the Herpes family of viruses. There are eight separate viruses within this family: Herpes simplex 1 and 2 (HV 1, HV 2), Varicella (HV 3), EBV (HV 4), Cytomegalovirus (HV 5), Herpes virus 6 (HV 6), Herpes virus 7 (HV 7), and Kaposi sarcoma-associated virus (HV 8) (1). HV1 and 2 are most commonly associated with oral and genital herpes. Varicella causes chickenpox and shingles and CMV causes CMV mononucleosis, which is similar to EBV mononucleosis but is often less severe. HV6 and HV7 are most commonly associated with roseola infantum. HV8 is not a known cause of acute illness but may cause Kaposi sarcoma and AIDS-related non-Hodgkin lymphomas. (1)
Infection and Transmission
HHV6 exists as two variations, identified as HHV-6A and HHV-6, and the vast majority of infections, primary and reactivations, are due to HHV-6B. (2) After a primary infection, the virus becomes latent in the body and can reactivate later in life. (4) It can remain latent in lymphocytes and monocytes, two types of white blood cells, and at low levels in organs. One of the primary locations is the salivary glands; “the virus replicates in the salivary glands and is shed in saliva, the recognized route of transmission.” (4) Other routes of transmission, including transplacental/intrauterine and via breast milk, have been investigated but not been proven. (4)
Symptoms of Acute Infection
HHV6B is most associated with roseola infantum, an infection that occurs typically before three years of age; little is known about infections with HHV-6A. (2) Infections occur most commonly in spring and fall and HHV6 usually has an incubation period of 5 to 15 days after exposure. (3) The first symptom may be a fever which begins “abruptly and persists 3 to 5 days without any localizing symptoms or signs. Despite the high fever, the child is usually alert and active.” (3) Swollen lymph nodes may develop and a rash appears primarily on the chest and abdomen after the fever subsides; rash may also be present on face, arms, and legs. (3) The rash may be hardly noticeable in mid cases and “in 70% of HHV-6 infections, the classic exanthem (rash) does not occur.” (3)
Primary infection in adults is rare because almost 100% of people have been infected as children. (2, 4) Adults can present with a mononucleosis-like syndrome (2) but the most serious symptoms occur in the immunocompromised, primarily organ transplant patients and patients with AIDS. (4) “HHV-6 is considered a major cause of opportunistic viral infections (in these populations) in whom HHV-6 infection/reactivation may culminate in rejection of transplanted organs and death. (4)
However, similar to other viruses in the herpes family, symptoms can be wide ranging. According to the HHV6 Foundation, “The following list is a summary of symptoms listed in persons with evidence for active HHV-6 infection:
- General Malaise: fatigue, chills, sweats, flu-like symptoms
- Cardiovascular: palpitations, tachycardia, arrhythmias
- Respiratory: oropharyngitis, coryza, cough, mild bronchitis, sore throat, intermittent wheezing
- Gastrointestinal: sialoadenitis, sicca syndrome, abdominal pain, indigestion, diarrhea
- Lymphatic: tonsillar hypertrophy, peripheral blood lymphocytosis, slight splenomegaly, mononucleosis-like disease
- Hematopoietic: anemia, thrombocytopenia
- Musculoskeletal: weakness, arthralgia, myalgia, SLE– or fibromyalgia-like symptoms
- Endocrine: various signs of thyroid dysfunction
- Skin: rash, eyelid & facial edema
- Central & peripheral nervous system: emotional lability, irritability, lack of concentration, headache, dizziness, loss of memory, chronic fatigue syndrome-type symptoms, paresthesia’s, peripheral neuropathy.” (5)
Complications of Acute Infection
Complications of primary HHV-6 infections are uncommon and rarely fatal. Case reports have described “invasion of the central nervous system (CNS) with seizures, hyperpyrexia, vomiting, diarrhea, cough, emophagocytic syndrome, fulminant hepatitis, disseminated infection, and hepatosplenomegaly. These complications suggest that the virus may spread to a number of organs, which may represent potential sites of virus persistence or latency and (subsequently) reactivation.” (4) HHV-6 has a strong “preference” to attack the nervous system and “neuroinvasion has been documented in infants with primary infection, in focal encephalitis, in children and adults with AIDS, in recipients of bone marrow transplants, as well as in immunologically competent children and adults.” (4)
Chronic Infection Concerns
Similar to EBV and CMV, there are several pathological conditions that have been linked to HHV6. According to the HHV6 Foundation, “the relationship between HHV-6 infection and some of these diseases is well established (but) the role of HHV-6 in many other conditions remains unclear. In addition to causing ‘acute’ disease, such as encephalitis, HHV-6 can also persist as a chronic infection, nearly undetectable by most current diagnostic tests. This subacute form of HHV-6 is likely to contribute to the pathology of many diseases associated with HHV-6.” 95)
This Foundation has a wealth of research and information on conditions possibly connected to HHV6, including the following list:
- “Autoimmune Diseases
- Cancer: Hodgkin’s Lymphoma, Gliomas, Cervical Cancer
- Chronic Fatigue Syndrome
- Cognitive Dysfunction: Delirium, Amnesia
- Encephalitis/ Encephalomyelitis
- Endocrine Disorders
- Epilepsy: Mesial/Temporal Lobe Epilepsy, Status Epilepticus
- Heart Disease: Myocarditis, Left Ventricle Dysfunction, Arteriopathies
- Hemophagocytic Conditions: Hemophagocytic Syndrome/ Histiocytosis
- HIV/AIDS Progression
- Hypersensitivity: Drug Induced Hypersensitivity Syndrome (DIHS), Drug Reaction with Eosinophilia & Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS)
- Immune Suppression: Bone Marrow Suppression
- Kidney Disease
- Liver Disease: Hepatitis, HIV/AIDS Progression
- Lung Disease: Organizing Pneumonia, Pneumonitis
- Multiple Sclerosis
- Rash & Roseola
- Seizures: Febrile Seizures, Status Epilepticus
- Transplant Complications: bone marrow suppression, Colitis/diarrhea, Delirium/CNS Dysfunction, Encephalitis/Amnesia, GVHD, Hemophagocytic syndrome, Hepatitis /Liver failure, Pneumonitis, Transplant Reactivation Overview
- Other Associations: SIADH, Hypogammaglobulinemia, Optic Neuritis, Microangiopathy, Mononucleosis, Uveitis” (5)
Reactivated HHV6 infection may also be present in inflammation of the blood vessels and collagen-vascular diseases and the implication of this association needs more research to identify if there is a possible causative effect from the virus. (5)
Diagnosis of HV6 infection is typically based on clinical signs and symptoms of roseola in young children and testing is rarely done in these cases. (2) Antibodies to HV6 can be tested to confirm diagnosis or if reactivation in suspected. (2) Because almost 100% of people have had an HHV6 infection in childhood, the main issue for diagnosis is not if they are present, but if they are elevated beyond what would be expected.
Because HHV6 is primarily latent within cells of the body, the virus itself or viral DNA will typically be “detected in plasma only briefly during the initial infection or acute reactivation…detection of HHV-6 DNA in plasma generally means the patient has an active infection.” (7) The HHV6 Foundation strongly notes that “a negative finding in the plasma does not rule out a localized active infection in an organ (e.g., uterus, brain, thyroid, liver). Persistent HHV-6 infections have been found in the liver, brain, lungs, heart tissue, and uterus with no trace of HHV-6 DNA in the plasma.” (7)
There are two types of typical antibody testing for HHV6: ELISA testing and IFA testing. According to the HHV6 Foundation, the ELISA test is less expensive than the IFA and is more commonly used by laboratories. (7) For example, Quest Diagnostics Lab and Providence Labs only run the IFA for HHV6 IgG and IgM antibodies (8, 9) while LabCorp only runs the ELISA test. (10) However, because the ELISA test was designed to indicate if antibodies are present, the HHV6 Foundation says that it is more difficult to use it to identify active infection since almost everyone will be positive on this test. Indications for active infection can be gained from this test if the result is extremely elevated and there are clinical indications supporting possible infection. (7) According to LabCorp’s information on interpreting results of the ELISA test in relation to the reference interval, “fourfold rises in titer are suggestive of either recent, primary, or reactivated infection. The presence of elevated titers to HHV-6 in the absence of responses to HAV, HBV, CMV, and EMV suggests that titer results are associated with high specificity.” (10)
The following table comes from the HHV-6 Foundation and provides a summary of the different types of testing for HHV6 and the general indications, advantages, and disadvantages of each test.
|TEST||Can it differentiate active from latent infection?||Comments|
|ELISA IgG test
Example: “positive >1.0”
|No. These results are intended to give only “yes/no” answers to whether you are exposed to the virus in the past.||An ELISA> 5 in an adult MIGHT be a clue of an active infection, but only the antibody tests done by IFA can tell you with precision how elevated the antibodies are.|
|IFA IgG test
Example: Titer 1:640
|If the titer is highly elevated relative to healthy controls, it means that the patient may have had a recent infection or has a current chronic infection. Titers vary by laboratory. Focus Diagnostics (Quest) has a median antibody titer between 1:80 and 1:160 for controls. Other labs have much lower control titers.||If the patient has an immune deficiency with low total IgG, then the antibody titer will not be elevated. If HHV-6 is the only antibody titer out of five viruses to be elevated above average, then this indicates possible HHV-6 infection.|
(ELISA or IFA)
|Yes. IgM only appears during an active infection or for 2-3 months after an active infection.||The absence of an IgM antibody does not mean you do not have an active infection. Chronic infections in various tissues can persist with no evidence of IgM.|
|PCR DNA test on plasma or serum
(qualitative or quantitative)
|Yes. HHV-6 is never found in plasma or serum unless there is an acute infection (or the individual has ciHHV-6). However, the absence of HHV-6 DNA in the plasma/serum does not mean that there isn’t a low-level persistent infection in the tissues (e.g. heart, thyroid, brain).||Any positive test result should be repeated with a quantitative test. Also, a whole blood test should be ordered to rule out chromosomally integrated HHV-6 (ciHHV-6) which occurs in <1% of the population.|
|Quantitative PCR DNA test on whole blood
Example: 1200 copies/ml
|Yes. If the viral load is >200 copies per ml or 20 copies per microgram of DNA then this is an active infection.||Healthy persons will have very low viral loads, typically less than 20 copies/ml in the whole blood. Usually this level is not detectable in a commercial lab.|
|Qualitative PCR DNA test on whole blood
Example: “Positive” with no numerical value given
|No. This test is useless for differentiating active from latent infection. Almost all healthy individuals have low levels of latent HHV-6B in the blood. On a sensitive nested PCR tests, at least a third of the normal population should test positive for HHV-6 latent DNA.||This test may be useful for determining if you have HHV-6A or HHV-6B but can’t tell you if the virus is active.|
Staining of tissue sections from biopsies, mounted on glass slides.
|YES. This test can tell you if the proteins expressed were from replicating virus. Only Coppe Labs and IKDT perform this service commercially.||This technique can also determine whether HHV-6A or HHV-6B is active. Analysis usually done on formalin fixed, paraffin embedded material.|
|Tissue Biopsy – qualitative||NO. This test cannot tell you if the virus is active. ViracorIBT offers a qualitative PCR test on tissues (liver, uterine, kidney, GI tract). Code: 6506||Depending on the lab, the virus can be typed. Specimens should be sent frozen overnight, with no liquid added.|
|Tissue Biopsy – quantitative||YES. This test can differentiate between low-level latent virus and active virus with high copy numbers.
Coppe Labs and ViracorIBT (Code 6505) and can test tissues sent frozen in a sterile container.
|Viracor requires 5 mg of material. Coppe can test 1 mg of material.
|ddPCR or Digital Droplet PCR to confirm ciHHV-6 status||This ddPCR test is done on whole blood and was introduced in 2013 by University of Washington specifically to identify ciHHV-6. It cannot identify active infection.||Patients should request this test when physicians want to confirm suspected ciHHV6.|
For the majority of patients, it appears that the IFA IgG is the best test to indicate active infection, and additional testing, including PCR testing for DNA and biopsies would be warranted only if specific symptoms indicated such. If the ELISA test is the only one available, LabCorp’s interpretation guidelines may be useful.
According to the Merck Manual, the “treatment of roseola infantum is generally symptomatic. Foscarnet or ganciclovir has been used to treat some immunosuppressed patients with severe disease, but controlled trials are lacking.” (3)
Treatment of HHV6 reactivation needs to be assessed based on a patient’s current symptoms, test results, and concerns for possible development of future conditions linked to HHV6. Because I see many patients with conditions associated with HHV6, I am very concerned about the developing body of research linking HHV6 as a potential causative factor for many of these diseases.
Disease occurs due to a combination of many different genetic and environmental factors. Some factors, such as our genes, we cannot change. There may be other factors medicine hasn’t identified yet. Since these are areas we cannot treat, I look to those known environmental factors that are significant risk factors. By reducing their impact, we can hopefully prevent future disease or reduce disease activity for those patients already diagnosed with these associated conditions.
Naturopathic medicine has many options for treating HHV6 both in terms of general anti-virals and options specifically designed for HHV6. Levels of immune-essential nutrients, such as vitamin A, vitamin D and zinc, can be optimized. Monolaurin is a byproduct of coconut oil and is commonly used as a general anti-viral. Lysine, which is often used to treat herpes simplex outbreaks, can also be used for HHV6, as can colostrum for patients who do not have issues with dairy. There are numerous herbs, including olive leaf, garlic, goldenseal, Echinacea, and grape seed, and mushrooms, including cordyceps, turkey tail, shiitake, and lion’s mane, that can be used individually or in combination formulas. Gemmotherapy preparations of several herbs are designed specifically to treat intra-cellular viruses, and essential oils can be added to herbal combinations. Treatments can also include supporting the T-regulatory cells of the immune system, including probiotics, fish oil, vitamin D, and glutathione.
When using any of these therapies, it is important to start with low doses and increase slowly to patient’s tolerance. Many people discuss “die-off” reactions with Lyme disease or candida overgrowth, and the same may be said for HHV6 infections. As such, a complete plan would also include supports for detoxification and elimination, and would balance and rotate any anti-viral therapies.
Because these anti-virals are generally safe and well-tolerated, and the impacts of autoimmune disease can be devastating, this is one situation where I personally err on the side of treatment, especially in cases where patients have very high antibody levels and/or multiple high viral antibody titers. My hope is that we can provide safe and relatively inexpensive treatment that could prevent a future health condition by treating a potential cause before symptoms arise.
Cytomegalovirus (CMV) is part of the Herpes family of viruses. There are eight separate viruses within this family: Herpes simplex 1 and 2 (HV 1, HV 2), Varicella (HV 3), EBV (HV 4), Cytomegalovirus (HV 5), Herpes virus 6 (HV 6), Herpes virus 7 (HV 7), and Kaposi sarcoma-associated virus (HV 8). (1) HV1 and 2 are most commonly associated with oral and genital herpes. Varicella causes chickenpox and shingles and CMV causes CMV mononucleosis, which is similar to EBV mononucleosis but is often less severe. HV6 and HV7 are most commonly associated with roseola infantum. HV8 is not a known cause of acute illness but may cause Kaposi sarcoma and AIDS-related non-Hodgkin lymphomas. (1)
Infection and Transmission
All herpes viruses can remain latent within the body and can reactivate; if the virus reactivates, it can be spread to others. People can also be infected by a different strain of the CMV virus than the strain of a previous infection. (2) “In the United States, nearly one in three children are already infected with CMV by age five and over half of adults by age 40 have been infected with CMV.” (2) Merck manual has those rates even higher, indicating that “60 to 90% of adults have CMV infection resulting in lifelong latent infection.” (4)
CMV spreads primarily through body fluids, including blood, saliva, urine, tears, semen, vaginal fluids, and breast milk (2, 3). CMV is spread from an infected person by:
- from direct contact with saliva or urine, especially from babies and young children;
- through sexual contact;
- from breast milk to nursing infants; and
- through transplanted organs and blood transfusions.
A woman who is infected with CMV can pass the virus to her developing baby during pregnancy. Women may be able to lessen their risk of getting CMV by reducing contact with saliva and urine from babies and young children because the saliva and urine of children with CMV have high amounts of the virus. A pregnant woman can avoid getting a child’s saliva in her mouth by, for example, not sharing food, utensils, or cups with a child. Also, she should wash her hands after changing diapers. These cannot eliminate her risk of getting CMV, but may lessen the chances of getting it.
Symptoms of Acute Infection
According to Mayo clinic, CMV “rarely causes problems in healthy people” (3) and initial CMV infection may cause no symptoms at all. Symptoms of a CMV infection can include fever, sore throat, fatigue, muscle aches, and swollen glands, and as such, may be referred to as CMV mononucleosis, given the similarity in symptoms with Epstein-Barr virus infection. (2, 3) According to Mayo Clinic, CMV may be less likely to cause swollen glands or enlarged spleen than EBV (3). Like an EBV infection, CMV infection can also cause hepatitis. (2)
The main issues are for pregnant women or people who are immunocompromised. In pregnancy, the virus can cross the placenta and infect the fetus, causing “brain, liver, spleen, lung, and growth problems” (2), abortion, stillbirth, or post-natal death (4). The most common health problem in babies born with congenital CMV infection is “hearing loss, which may be detected soon after birth or may develop much later in childhood.” (2) Perinatal infections can also occur during or soon after birth can also be an issue. (3) “Babies with congenital CMV who are sick at birth tend to have significant signs and symptoms, including:
- Premature birth
- Low birth weight
- Yellow skin and eyes (jaundice)
- Enlarged and poorly functioning liver
- Purple skin splotches or a rash or both
- Abnormally small head (microencephaly)
- Enlarged spleen
- Seizures” (3)
In the immunocompromised, the infection can affect eyes, lungs, liver, stomach, intestines, and brain and can be much more serious, including being fatal. (3)
Chronic Infection Concerns
Most of the sources on CMV infection indicate that long-term complications occur in congenital infections and immunocompromised patients, and that “rare complications for healthy adults include problems with the digestive system, liver, brain and nervous system”. (3) However, emerging research is showing that CMV infection may be a significant contributor to cardiovascular disease, diabetes and metabolic syndrome, autoimmune diseases, and cancer.
A nationally representative population-based study from 1999 to 2002 found that being seropositive for a CMV infection was associated with high blood pressure in women. (5) This meta-analysis included “three studies involving 9657 patients…and the results showed a significantly increased risk of EH (essential hypertension) in patients with CMV infection.” (6) The authors concluded that the association was significant to say that “CMV infection is a possible cause of EH.” (6) Three other studies from 2009, 2016, and 2017 found:
- “CMV infection is a risk factor for increased arterial blood pressure, and is a co-factor in aortic atherosclerosis” and contributes to the production of pro-inflammatory mediators in the body. (7)
- “CMV infection is associated with an increase in SBP (systolic blood pressure) in individuals at age 70 years. The magnitude is comparable to environmental variables such as obesity, diabetes or high salt intake. This is the first evidence to show that a chronic infection may be an important determinant of blood pressure and could have significant implications for the future management of hypertension.” (8)
- “CMV IgG antibody titers were positively correlated with arterial BP, greater grade of hypertension and hypertensive TOD (target organ damage), and CRP and IL-6 levels. In the Han Chinese population, high CMV IgG titers are associated with the progression of hypertension and hypertensive TOD. CMV IgG titer >4.25 U could be an independent predictor of hypertension and progression of hypertension, while that >4.85 U could be an independent risk factor for hypertensive TOD. The underlying mechanism may be largely mediated by chronic inflammation.” (9)
CMV infection may also be linked to cardiovascular disease and “high levels of antibodies against CMV seem to be associated with clinically manifested atherosclerotic disease, which may indicate repeated reactivation of latent infection in many of these patients.” (10) A 2010 study found the “proinflammatory influence of persistent CMV on the microvasculature, and suggest that CMV infection enhances microvasculature susceptibility to both inflammatory and thrombogenic (clot forming) responses caused by hypercholesterolemia (high cholesterol). (11)
Diabetes and Metabolic Syndrome
A 2012 study showed that “adults ages 85 and over who were infected with cytomegalovirus were about twice as likely to have Type 2 diabetes compared with those not infected.” (12) The authors stated that their results indicated an association, not necessarily a causation, and that their results may not apply to other populations.
A 2017 report looked at extremely obese women and women of normal weight, all of whom were positive for CMV. Findings indicated women positive for CMV were more likely to develop metabolic syndrome than women who were negative. (13) Additionally, the extremely obese women were less likely than women of normal weight to develop metabolic syndrome and the authors stated that “the key initiator of metabolic syndrome is chronic, low-grade inflammation, rather than obesity per se… (and) consequently, it is worth exploring whether alternative sources of chronic, low-grade inflammation, other than obesity, are contributing to the burden of [metabolic syndrome].” (13)
Literature suggests a causative linkage between HCMV and systemic lupus erythematosus (SLE), systemic sclerosis (SSc), diabetes mellitus type 1, and rheumatoid arthritis (RA). (14) Asian scientist reported in 2016 that CMV infection may cause autoimmune diseases by destroying natural killer cells. The CMV induces an antibody that also targets NK cells, and the “reduction of NK cells is characteristic of a bunch of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and primary Sjogren’s syndrome.” (15) CMV infection can also aggravate autoimmune mediated neuro-inflammation and demyelination in MS (16) and a 2017 study indicated that “CMV-DNA copy numbers and concurrent infections are predictors of in-hospital mortality in CMV-infected patients with autoimmune diseases.” (17)
CMV has also been considered a factor in the development of cancer. A 2016 study “suggested a statistically association between the virus infection and an increased risk of colorectal cancer” (18) and a 2014 study from the USC School of Dentistry identified CMV as a cause of the most common salivary gland cancers.” (19) Other studies identify CMV infection as having a “modulatory effects on tumours, increasing their malignancy. Manipulation of the host cell cycle as well as the immune response may promote the replication and propagation of the virus and as a consequence of that interruption of the normal checks that block cancer growth.” (20) There are many questions still surrounding the role of CMV in cancer and more research needs to be done to understand the connections and associations that have been seen so far. “In the last decade, multiple investigators have identified HCMV infection specifically in human malignancies including malignant glioma, colon cancer, breast cancer, prostate cancer, medulloblastoma, salivary gland (mucoepidermoid) carcinoma, neuroblastoma, and rhabdomyosarcoma. Considerable controversy exists as to whether a) HCMV infection is actually present in these malignancies, and b) if present, whether HCMV is involved in the initiation and/or promotion of the tumors. Should HCMV persistently infect various human cancer types, it is possible that multiple viral-driven oncogenic mechanisms may potentially be involved.” (21)
In the nervous system, CMV can cause encephalitis and may be associated with Guillain-Barre syndrome. (22) CMV can also cause symptoms in the digestive tract, including ulcers, diarrhea, intestinal bleeding and gastroenteritis/colitis, as well as symptoms in the lung, including shortness of breath, pneumonia, and low oxygen. (23) Many of the reports of these symptoms are from immunocompromised patients; however, they provide information about the body systems most affected by the virus, possibly with less severe manifestations in immunocompetent people.
This handout is in no way a full review of the literature on the effects of CMV infection. However, given the growing research showing associations and/or potential causes between CMV and these major conditions, the complications or long-term effects of CMV infection and reactivation need to be taken more seriously even for otherwise “healthy” patients.
Diagnosis of acute CMV infection is based on symptoms and signs and bloodwork. Often patients present with symptoms of mononucleosis (often less sore throat than EBV infection) but have a negative monospot test. (4) Antibodies specifically for CMV can be tested to identify possible CMV infection. A complete blood count may also show atypical lymphocytes; it is important to know that “atypical lymphocytes may also be present in HIV or CMV infection, hepatitis B, influenza B, rubella, or other viral illnesses… however, very high atypical lymphocyte counts are typically seen only in primary EBV and CMV infection.” (24) Because CMV can also cause elevated liver enzymes, blood testing for hepatitis viruses may also need to be done. (4)
Treatment of CMV needs to be assessed based on a patient’s current symptoms, test results, and concerns for possible development of future conditions linked to CMV. According to Western medicine, there is no treatment available for CMV infection except for the use of a few specific antivirals for severe infections in in babies and for the immunocompromised. (2, 4) Most sources also say that no treatment is needed for healthy adults. However, I am very concerned about the developing body of research linking CMV as a potential association or causative factor for cardiovascular disease, metabolic syndrome and diabetes, many common autoimmune diseases, and cancer. These diseases occur due to a combination of many different genetic and environmental factors. Some factors, such as our genes, we cannot change. There may be other factors medicine hasn’t identified yet. Since these are areas we cannot treat, I look to those known environmental factors that are significant risk factors. By reducing their impact, we can hopefully prevent future disease or reduce disease activity for those patients already diagnosed with autoimmune conditions.
Although most adult infections are due to reactivation of a previous infection, preventative measures can be taken to avoid infection, including washing hands thoroughly and often, avoiding contact with body fluids or sharing food or drinks, cleaning toys and countertops, and practicing safe sex. (3)
Naturopathic medicine has many options for treating CMV both in terms of general anti-virals and options specifically designed for CMV. Levels of immune-essential nutrients, such as vitamin A, vitamin D and zinc, can be optimized. Monolaurin is a byproduct of coconut oil and is commonly used as a general anti-viral. Lysine, which is often used to treat herpes simplex outbreaks, can also be used for CMV, as can colostrum for patients who do not have issues with dairy. There are numerous herbs, including olive leaf, garlic, goldenseal, Echinacea, and grape seed, and mushrooms, including cordyceps, turkey tail, shiitake, and lion’s mane, that can be used individually or in combination formulas. Gemmotherapy preparations of several herbs are designed specifically to treat intra-cellular viruses, and essential oils can be added to herbal combinations. Treatments can also include supporting the T-regulatory cells of the immune system, including probiotics, fish oil, vitamin D, and glutathione.
When using any of these therapies, it is important to start with low doses and increase slowly to patient’s tolerance. Many people discuss “die-off” reactions with Lyme disease or candida overgrowth, and the same may be said for CMV infections. As such, a complete plan would also include supports for detoxification and elimination, and would balance and rotate any anti-viral therapies.
Because these anti-virals are generally safe and well-tolerated, and the impacts of the associated diseases can be devastating, this is one situation where I personally err on the side of treatment, especially in cases where patients have very high antibody levels. My hope is that we can provide safe and relatively inexpensive treatment that could prevent a future autoimmune condition by treating a potential cause before symptoms arise.
Mast Cell Activation Disorder
Mast cell activation disorder (MCAD), also called mast cell activation syndrome (MCAS), is a condition of aberrant mast cell activity in response to stimuli that normally do not activate mast cells or with excessive mast cell responses.
Mast Cell Biology
Mast cells are cells of the immune system that derive from bone marrow. Immature cells are released into the blood and travel to different locations throughout the body, directed by different chemicals produced by other immune cells. When they reach their destinations, they differentiate into their mature forms and remain local; they do not return to general circulation.
Mast cells are found in all tissues except the central nervous system and the retina of the eye, and can be divided into “mucosal” and “connective tissue” types. (1,2) Mucosal mast cells are found in the lining of the organs and tissues and the connective tissue types are found in high numbers in connective tissues, including tendons, ligaments, cartilage, and fat.
Mast cells store a huge number of different chemicals. The most well-known ones include histamine, interleukins, proteoglycans (e.g., heparin), tryptase, proteases, other enzymes, and cytokines, which are stored in sacs or granules. When the mast cell is stimulated by a trigger, they release the contents of their granules into the surrounding tissues, which produce local responses characteristic of mediator(s) released. (3) On stimulation, mast cells can also synthesize new chemicals in addition to the pre-formed ones in the granules. Mast cells can be triggered by allergens causing an IgE antibody reaction with receptors on the surface of the mast cell. However, mast cells can be affected by triggers other than IgE, and the amount, duration, and rate of the response will depend on the type of trigger. (4)
The chemicals released by mast cells have a wide range of effects. Histamine is most often associated with allergic responses, but it also causes the release of gastric acid in the stomach, acts as a neurotransmitter in the brain, and a communication chemical for many cells of the immune system. (5) Heparin prevents clot formation and tryptase plays an important role in inflammation. Proteases are enzymes that break down proteins, which can be important in destroying bacteria or tissue remodeling from wounds. Cytokines are communication chemicals of the immune system. Other mast cell chemicals may oppose inflammation or regulate the release of mediators from the granules and can enhance or suppress their actions once released.
Mast cells play an important role in immune function. They can exert a positive (enhancing) or negative (suppressing) effect on other cells of the immune system, changing the overall immune response. They serve as a first-line defense and are involved in the development and maturation of T cells. (6) They can help clear bacterial infections, and enhance immune reactions by modulating inflammatory responses to infections. (7) Mast cells also play a key role in clearing the chemicals produced by the immune system to kill infections, which is important because many of these chemicals can have adverse effects at high concentrations. (7) Mast cells can also have protective functions against different venoms and parasites and can help prevent sepsis-related mortality associated with infections. (8) Several of the chemicals released by mast cells can promote blood vessel formation, which is important in wound healing. (9)
Overall, mast cells can have a powerful effect on every system of the body. These effects can be protective or harmful, depending on the type and amount of the chemicals they release into the surrounding area.
Other Mast Cell Related Conditions
Most commonly, mast cells are associated with allergies because of the histamine release due to the IgE antibody trigger. With exposure to an allergen, people generally have symptoms in the system that contacted the allergen, i.e., respiratory symptoms from an inhaled allergen, or skin symptoms from a topical exposure. Exposure to food allergens also most commonly cause gastrointestinal symptoms but can cause more systemic symptoms if the allergen is absorbed into the body through the intestines.
Other conditions associated with mast cells are systemic mastocytosis (SM) and possibly histamine intolerance. SM differs from MCAD in that SM is a group of disorders characterized by increased actual numbers of mast cells and infiltration of mast cells into the skin, other organs, or both. (10) SM is caused by a gene (KIT-816V) mutation that allows for uncontrolled proliferation of mast cells. “This mutation isn’t seen consistently in MCAD but has supported theory that there may be mutations affecting mast cell biology. A genetic cause is a likely factor because the risk of MCAD in patients with a relative with MCAD is triple that of the general population.” (11) Dr. Lawrence Afrin, one of the main researchers into MCAD, theorizes that there are “one of more inheritable ‘genetic fragility factors’ which interact with different stressors…to cause additional non-inheritable mutations” (11) and that combination of mutations can lead to MCAD.
Histamine intolerance can cause many similar symptoms to MCAD but appears to be more limited to histamine, rather than the whole variety of mast cell chemicals, and may have more to do with an inability to breakdown histamine than a condition of mast cell instability. (12)
Symptoms of MCAD
Symptoms of MCAD can be extremely varied and can occur in every system of the body. Symptoms are often low-grade and chronic and can be episodic with periods of calm and flares. (13) One of the most important characteristics is that there are multiple symptoms in multiple systems of the body. (13)
Dr. Afrin and colleagues have developed an extensive list of symptoms they have observed with patients and includes the following:
- Constitutional: fatigue/malaise, weakness, “chronic fatigue syndrome”, subjective and/or objective increased or decreased temperature, “sense of feeling cold much of the time”, sweats (not always nocturnal), flushing, redness or paleness, increased or decreased appetite, early fullness when eating, weight gain or loss, chemical and/or physical environmental sensitivities (often odd)
- Skin: rashes , freckles, dry skin, warts, skin tags, inflammation of hair follicles, ulcers, eczema, itching, sometimes triggered by exposure to water, stretch marks, streaking on scratching the skin, hair thinning and loss, brittle nails, longitudinal ridges in nails, poor wound healing
- Lymph: swollen lymph nodes, often changing in size or location, sometimes no symptoms but may be tender, left upper quadrant discomfort in abdomen
- Lung: nasal inflammation, sinusitis, throat inflammation, bronchitis, lung inflammation or pneumonitis (often confused with infectious pneumonia), cough, difficulty breathing/dyspnea (often low-grade, “I just can’t catch a deep breath”), wheezing, obstructive sleep apnea, pulmonary hypertension
- Cardiovascular: lightheadedness, weakness, dizziness, vertigo, fainting, postural orthostatic tachycardia syndrome or neurocardiogenic fainting, high and/or low blood pressure, palpitations, abnormal heart rhythms, chest discomfort or pain, atherosclerosis/spasm, heart failure , aneurysms, hemorrhoids, varicose veins, aberrant angiogenesis (cherry angiomas, hemangiomas, arteriovenous malformations, spider veins) , migratory swelling (often non-dependent and with normal cardiac and renal function)
- Gastrointestinal: swallowing air, swelling (angioedema) in any segment of the GI, difficulty swallowing, bloating/gas, abdominal pain/inflammation (often migratory) , queasiness, nausea, vomiting (sometimes “cyclical”), diarrhea and/or constipation (often alternating), malabsorption (more often selective micronutrient than general protein-calorie malabsorption), abdominal edema/water retention, gastroesophageal reflux disease (often “treatment-refractory”) , inflammatory or irritable bowel syndrome, microscopic colitis
- Genito-urinary: inflammation of urethra, bladder, or kidney (often migratory), inflammation of vagina or prostate, chronic kidney disease, endometriosis, chronic low back pain or side pain, hydronephrosis , infertility, erectile dysfunction, decreased libido , miscarriages
- Musculo-skeletal: muscle pain, often diffusely migratory, fibromyalgia , arthritis (typically migratory), joint laxity/hypermobility, diagnosis of Ehlers-Danlos Syndrome Type III, osteoporosis/osteopenia, osteosclerosis, musculoskeletal pain poorly responsive to NSAIDs and narcotics, possible elevated creatine kinase
- Neurologic: headache (esp. migraine), peripheral sensory and/or motor issues including abnormal sensations, tics, tremors (typically resting) , chronic inflammatory demyelinating polyneuropathy, seizure disorders (can be “treatment-refractory”), pseudoseizures, dysautonomia
- Endocrine/Metabolic: abnormal electrolytes (including magnesium), abnormal liver function tests, delayed puberty, menstrual cramps, hypothyroidism or hyperthyroidism, abnormal cholesterol/lipids, elevated ferritin, selective vitamin and/or other micronutrient deficiencies
- Immune: hypersensitivity reactions, autoimmunity, increased susceptibility to infection, elevated or decreased levels of one or more types of immunoglobulin
- Blood: elevated red blood cell count (polycythemia), anemia (may be macrocytic, normocytic, or microcytic), high or low white blood cell counts, high monocytes, eosinophils or basophils, high or low platelets, clotting disease, easy bruising/bleeding
- Psychiatric: mood disturbances (g., anger, depression), bipolar affective disorder, attention deficit-hyperactivity disorder, post-traumatic stress disorder, anxiety and panic, psychoses, memory difficulties, word-finding difficulties, other cognitive dysfunction, sleep disruptions (13)
Research is being done into the potential causative role of mast cells in plaque build-up in arteries, because of the pro-inflammatory chemicals (14) as well as in cancer, both from the inflammatory and blood-vessel building effects. (15) However, the net role of mast cells in cancer development may benefit either the host or the tumor, depending on a variety of factors, including genetics, overall immune health, and the micro-environment of the tumor location. (15)
Because of the effects on the immune system, MCAD may also be associated with an increased risk of autoimmune disease and chronic infection. (11) There may also be quality of life issues and narcotics risk with chronic pain and malnutrition from intestinal inflammation. (11).
Diagnosis of MCAD
Diagnosis of MCAD is based on symptoms, history, lab testing, response to MCAD-based treatment, and ruling out other possible conditions. Symptoms and history can be identified by the patient interview and the checklist developed by Dr. Afrin and colleagues. (13) Lab testing can be difficult because of the challenges with many of the lab tests. First, many of the tests require very specific handling procedures because several of the tests are not heat-stable. If the samples are not kept chilled for the entire time between collection and analysis, false negative results are highly possible. Once the sample is provided to the lab, it may be difficult to know if the sample was kept chilled the entire time.
Second, some of the tests need to be run during a flare-up of symptoms which can be difficult for collection; results from samples collected outside a flare-up may show falsely low results. Third, the samples are collected from blood and/or urine, which reflect conditions throughout the body. A person could still have very significant local mast cell effects while these systemic test results could be negative. Additionally, many of the local labs I have contacted do not even run some of the tests recommended for MCAD diagnosis. Given these challenges, I discuss with each patient the advantages and disadvantages of running the different tests that could give us information about MCAD. Many patients also opt for a trial of MCAD-based therapy to see if symptoms improve.
Treatment of MCAD
MCAD is an extremely complex condition with a myriad of presentations. As such, I follow the treatment principles outlined by Dr. Afrin:
- “#1: get patients feeling better, not perfect and not all the time
- #2: be patient and persistent and use a methodical approach
- #3: change only one thing at a time
- #4: start with the cheapest medications and change only as necessary
- #5: if a patient destabilizes, review what changed over the weeks before to try to identify a cause
- #6: remember that active and inactive ingredients of medications can cause flare-ups
- #7: simpler is better
- #8: if one drug in one class doesn’t work, don’t give up on all the drugs within that class (check inactive ingredients)
- #9: identify and avoid triggers
- #10: remember all the other preventative screenings and general health measures” (11)
It is important to keep in mind that “with the exception of classic histamine-related symptoms, at present it is virtually impossible to predict effective therapy for the individual MCAS patient based on the presenting symptoms and findings.” (11)
Identifying and avoiding triggers is crucial to treatment. Avoiding a flare-up is much easier than trying to calm it once it has started. However, potential triggers can be extremely varied and the list I’ve compiled from a variety of sources may include:
- Stress, sympathetic activation, accidents, surgery
- Sleep deprivation
- Sun/heat, temperature changes (especially sudden), pressure/touch
- “caine” anesthetics, NSAIDs, narcotics, active or inactive ingredients in any medications
- Aspirin (especially for tryptase-driven issues)
- Alcohol, high sugar
- Oxidative stress
- Zinc or vitamin C deficiency
- Excess salt
- Chronic infection
- Exposure to allergens
- Hormone imbalances
Specific treatment for MCAD can include pharmaceuticals, naturopathic treatments, and other supportive therapies. Pharmaceutical treatments may include:
- steroids to reduce inflammation;
- mast cell stabilizers (ketotifen and cromolyn sodium);
- histamine blockers for histamine-related symptoms;
- leukotriene blockers; and
- medications to manage symptoms, such as pain or anxiety. (11)
There are some medications that have some anecdotal use, and some that theoretically could be helpful but there is no MCAD-specific data on their efficacy. (11) There are also some medications that are still in clinical trials and could become options in the future.
Naturopathic treatments include:
- evaluation of diet, especially for high histamine, high histidine, and high salicylate foods;
- evaluation of intestinal bacterial balance because certain types of bacteria produce histamine while others break it down (16);
- herbal and nutritional mast cell stabilizers;
- anti-inflammatory herbs and nutrients;
- treatment to support histamine breakdown, especially via methylation; and
- lactoferrin especially for tryptase and heparin.
Other therapies may be non-medication ideas for symptom support and/or stabilization. For example, for a patient with low blood pressure, maintaining consistently adequate water intake and electrolytes along with wearing compression garments might be helpful.
I also feel that part of naturopathic treatment is patient advocacy. The understanding of MCAD in the medical field is still emerging and many practitioners are not aware of the condition or diagnosis. Many patients are told their symptoms are “all in their heads”; while MCAD can cause many neurologic and psychiatric symptoms, there is a true physiological basis for what MCAD patients are experiencing.
Understanding and treating MCAD takes patience and perseverance, and with both, significant improvements can be made for people who never had answers before.
(11) Afrin, L. Never Bet Against Occam: Mast Cell Activation Disease and the Modern Epidemics of Chronic Illness and Medical Complexity. 2016
(13) Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol2014; 3(1): 1-17
Epstein-Barr virus (EBV) is part of the Herpes family of viruses. There are eight separate viruses within this family: Herpes simplex 1 and 2 (HV 1, HV 2), Varicella (HV 3), EBV (HV 4), Cytomegalovirus (HV 5), Herpes virus 6 (HV 6), Herpes virus 7 (HV 7), and Kaposi sarcoma-associated virus (HV 8) (1). HV1 and 2 are most commonly associated with oral and genital herpes. Varicella causes chickenpox and shingles and CMV causes CMV mononucleosis, which is similar to EBV mononucleosis but is often less severe. HV6 and HV7 are most commonly associated with roseola infantum. HV8 is not a known cause of acute illness but may cause Kaposi sarcoma and AIDS-related non-Hodgkin lymphomas. (1)
Infection and Transmission
All herpes viruses can remain latent within the body and EBV infects the B cells of the immune system. EBV spreads primarily through body fluids, most commonly through saliva (3); it can also be transmitted through sexual contact, blood transfusions, and organ transplants (3). EBV does not survive on surfaces but it “can be spread by using objects, such as a toothbrush or drinking glass that an infected person recently used. The virus probably survives on an object at least as long as the object remains moist.” (3)
An infected person can shed the virus for weeks before symptoms appear and “if the virus reactivates, (a person) can potentially spread EBV to others no matter how much time has passed since the initial infection.” (3) People with reactivated infections may also be able to transmit EBV to other people even if they themselves do not have active symptoms. (1)
Symptoms of Acute Infection
Half of children are infected with EBV before the age of 5 (2) and “EBV infections in children usually do not cause symptoms, or the symptoms are not distinguishable from other mild, brief childhood illnesses.” (3)
Symptoms of infectious mononucleosis develop most often in older children and adults and include fever, sore throat (pharyngitis), and lymph node swelling (adenopathy). (2) The lymph node swelling is usually symmetrical, can include any group of lymph nodes, and may be the only symptom (2) Patients may also experience enlargement of the spleen and/or liver, swelling around the eyes, and rash.
The typical symptoms of acute infectious mononucleosis can be similar to those of other infections, and patients with this presentation should also be evaluated for primary HIV infection, cytomegalovirus infection, “toxoplasmosis, hepatitis B, rubella, or atypical lymphocytes associated with adverse drug reactions.” (2)
Complications of Acute Infection
Patients typically recover completely from EBV mononucleosis but fatigue can last for months after other symptoms resolve. (2, 3) Acute complications of the infection are rare but may be significant and can include:
- Neurologic complications:encephalitis, seizures, Guillain-Barré syndrome, peripheral neuropathy, viral meningitis, myelitis, cranial nerve palsies, and psychosis
- Hematologic complications: granulocytopenia, thrombocytopenia, hemolytic anemia
- Splenic rupture
- Respiratory complications: upper airway obstruction due to adenopathy
- Hepatic complications: elevated aminotransferase levels, jaundice (2)
Chronic Infection Concerns
In addition to causing infectious mononucleosis, EBV is known as a potential cause of hepatitis, encephalitis, nasopharyngeal carcinoma, Hodgkin lymphoma, and Burkitt lymphoma (1, 2). While EBV may remain latent for many people, significant research is being done into links between EBV and many autoimmune diseases. A search of the NIH website for research done in just the last 5 years showed studies linking EBV as a potential cause of the development and exacerbation of multiple sclerosis (4, 5, 6), lupus (5), rheumatoid arthritis (7, 8), oral lichen planus (8), Sjögren’s syndrome (7, 9), Hashimoto’s and Grave’s diseases (autoimmune thyroid diseases) as well as possibly primary thyroid lymphoma (10). “Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), have a potential causative link with EBV” (11) as do “interstitial pneumonia, malignant lymphoma, and coronary aneurysm.” (12)
The findings of a 2015 study indicated that EBV infections can become life-threatening in rare cases, but in contrast, “a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood.” (13) This indicates that EBV may cause significant immune disruption, including cancers, in otherwise immune healthy patients, through routes and interactions with other factors that we have not yet identified. Given that the vast majority of the population has been infected with EBV but not everyone develops these conditions, we know that EBV infection alone is not the cause. However, we also do not know what the characteristics are that would cause any individual person to go on to develop one of these conditions with EBV as one of the causative factors.
Diagnosis of acute infectious mononucleosis is based on symptoms and signs and a positive heterophile antibody (monospot) test. Patients should know that “heterophile antibodies are present in only 50% of patients less than 5 years old and in about 80 to 90% of adolescents and adults with infectious mononucleosis.” (2) This test may also give a false-positive result in patients with acute HIV infection. (2) If there is high suspicion of mono but a negative monospot, it is worth repeating the test after 7 to 10 days, as the antibody levels rise in the 2nd and 3rd weeks of illness. (2) A complete blood count may also show atypical lymphocytes; it is important to know that “atypical lymphocytes may also be present in HIV or CMV infection, hepatitis B, influenza B, rubella, or other viral illnesses… however, very high atypical lymphocyte counts are typically seen only in primary EBV and CMV infection.” (2)
Laboratory testing may also include antibodies to EBV. There are four different types of EBV antibodies: IgG antibodies for Early Antigen (EA-IgG), IgM antibodies to the viral capsid (VCA-IgM), IgG antibodies to the viral capsid (VCA-IgG), and IgG antibodies to the nuclear antigen (EBNA-IgG). These represent different phases of the immune system’s response to different parts of the virus itself. Most labs provide a table to interpret the pattern of a patient’s results. The following is from Labcorp:
|EBV Interpretation Table (14)|
|Key — Antibody present: + Antibody absent: −|
|Acute primary infection||+||±||+||−|
If all these antibody tests are negative, then it means the patient has never been exposed to EBV. A positive titer for VCA-IgM indicates a primary EBV infection because the IgM antibodies are the first to appear and the first to disappear, typically within 3 months after infection. (2) VCA-IgM antibodies can also reappear in a reactivated infection, but are not always present. The EA-IgG and VCA-IgG antibodies develop after the IgM antibodies and there can be a time of overlap between the presences of these two types of antibodies. The EBNA-IgG antibodies are the last to appear and VCA-IgG and EBNA-IgG persist for life.
According to the Merck Manual, “over 90% of adults are seropositive for EBV.” (2) This means that 90% of adults in the general population have been exposed to EBV and will show positives for past infection. This is a very different pattern than that of patients with active infection. Additionally, while the lab table indicates that the EA-IgG is positive for a reactivated infection, Dr. Oethinger , the director of microbiology at Providence Laboratory, indicated in personal communication that “the EA doesn’t need to be positive again during reactivation.” (15) This means that the pattern between past and reactivated infections can be difficult to differentiate and individual patients must be evaluated based on symptoms as well as potential risks for future issues.
Treatment of EBV needs to be assessed based on a patient’s current symptoms, test results, and concerns for possible development of future conditions linked to EBV. Because I see many patients with autoimmune conditions, I am very concerned about the developing body of research linking EBV as a potential causative factor for many common autoimmune diseases.
Autoimmune diseases occur due to a combination of many different genetic and environmental factors. Some factors, such as our genes, we cannot change. There may be other factors medicine hasn’t identified yet. Since these are areas we cannot treat, I look to those known environmental factors that are significant risk factors. By reducing their impact, we can hopefully prevent future disease or reduce disease activity for those patients already diagnosed with autoimmune conditions.
Western medicine has no options for treatment of EBV infections except supportive care and corticosteroids possibly for severe disease. (2) The anti-virals that are effective for other herpes family viruses (especially acyclovir) do not appear effective against EBV. Studies have shown that acyclovir reduces shedding of EBV in saliva, but it does not change any single symptom or course of disease and viral titers returned to pre-treatment levels one to three weeks after cessation of therapy. (16, 17, 18) These are older studies, but as of February 2016, the Merck Manual still states “there is no convincing evidence to warrant (acyclovir’s) clinical use” for EBV infection. (2) The Merck Manual does list two other medications as showing possible activity against EBV: cidofovir and foscarnet. However, both of these medications are only given IV and are limited by significant kidney toxicity. (2) Therefore, they would be reserved for the most severe cases.
Naturopathic medicine has many options for treating EBV both in terms of general anti-virals and options specifically designed for EBV. Levels of immune-essential nutrients, such as vitamin A, vitamin D and zinc, can be optimized. Monolaurin is a byproduct of coconut oil and is commonly used as a general anti-viral. Lysine, which is often used to treat herpes simplex outbreaks, can also be used for EBV, as can colostrum for patients who do not have issues with dairy. There are numerous herbs, including olive leaf, garlic, goldenseal, Echinacea, and grape seed, and mushrooms, including cordyceps, turkey tail, shiitake, and lion’s mane, that can be used individually or in combination formulas. Gemmotherapy preparations of several herbs are designed specifically to treat intra-cellular viruses, and essential oils can be added to herbal combinations. Treatments can also include supporting the T-regulatory cells of the immune system, including probiotics, fish oil, vitamin D, and glutathione.
When using any of these therapies, it is important to start with low doses and increase slowly to patient’s tolerance. Many people discuss “die-off” reactions with Lyme disease or candida overgrowth, and the same may be said for EBV infections. As such, a complete plan would also include supports for detoxification and elimination, and would balance and rotate any anti-viral therapies.
Because these anti-virals are generally safe and well-tolerated, and the impacts of autoimmune disease can be devastating, this is one situation where I personally err on the side of treatment, especially in cases where patients have very high antibody levels. My hope is that we can provide safe and relatively inexpensive treatment that could prevent a future autoimmune condition by treating a potential cause before symptoms arise.
(4) Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis (https://www.ncbi.nlm.nih.gov/pubmed/24493474)
(5) Epstein-Barr virus in multiple sclerosis. (https://www.ncbi.nlm.nih.gov/pubmed/25162741)
(6) Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection. (https://www.ncbi.nlm.nih.gov/pubmed/26046559)
(7) Epstein-Barr virus in systemic autoimmune diseases (https://www.ncbi.nlm.nih.gov/pubmed/24062777)
(8) Epstein-Barr virus and its association with rheumatoid arthritis and oral lichen planus. (https://www.ncbi.nlm.nih.gov/pubmed/26980953)
(9) Connective tissue diseases: Epstein-Barr virus in Sjögren’s syndrome salivary glands drives local autoimmunity. (https://www.ncbi.nlm.nih.gov/pubmed/24934188)
(10) The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases. (https://www.ncbi.nlm.nih.gov/pubmed/25931043)
(11) Epstein-barr virus as a trigger of autoimmune liver diseases. (https://www.ncbi.nlm.nih.gov/pubmed/22693505)
(12) Possible autoimmune hepatitis induced after chronic active Epstein-Barr virus infection. ( https://www.ncbi.nlm.nih.gov/pubmed/26183510)
(13) The immunology of Epstein-Barr virus-induced disease. (https://www.ncbi.nlm.nih.gov/pubmed/25706097)
(15) personal communication, Dr. Kimberly Hindman and Dr. Oethinger
(16) Acyclovir treatment in primary Epstein-Barr virus infection. A double-blind placebo-controlled study. (https://www.ncbi.nlm.nih.gov/pubmed/3006226)
(17) Acyclovir and Epstein-Barr virus infection. (https://www.ncbi.nlm.nih.gov/pubmed/6313591)
(18) Acyclovir treatment in infectious mononucleosis: a clinical and virological study. (https://www.ncbi.nlm.nih.gov/pubmed/3036715)
What is pyroluria?
Pyroluria is a genetic disorder caused by abnormal hemoglobin synthesis. Hemoglobin is the protein in red blood cells that contains iron and carries oxygen throughout the body. During hemoglobin synthesis, by-product compounds called kryptopyrroles are formed. This is a normal process even though there is no known function of kryptopyrroles in the body. However, in people with pyroluria, these compounds are produced to excess, especially under stress, and create deficiencies of vitamin B6 (pyridoxine) and zinc. Because of this, most of the signs and symptoms associated with pyroluria are due to deficiencies of B6 and zinc.
Vitamin B6 and zinc are essential in the body. Vitamin B6 is required for more than 100 enzyme reactions in the body. It is specifically required for:
- Converting food into glucose for energy;
- Niacin production;
- lipid metabolism,
- carnitine synthesis,
- production of neurotransmitters serotonin, dopamine, norepinephrine, histamine, and GABA;
- functioning of the immune system;
- formation of red blood cells;
- control of homocysteine (along with B12 and folate); and
- hormone modulation.
Zinc is also essential for enzyme function and more than 50 enzymes in the body contain zinc. Zinc is important for:
- cell growth and replication;
- hormone activity and reproduction;
- vision, especially night vision;
- immune function;
- protein metabolism;
- wound healing and blood clot formation;
- breakdown of carbohydrates;
- thyroid function;
- resistance to stress;
- maintaining cognitive function, memory, and learning; and
- normal appetite, taste, and smell.
Moderate zinc deficiency is also associated with disorders of the intestine which interfere with food absorption (malabsorption syndromes), which can cause additional symptoms and health conditions. This may be why tendency to iron deficiency or low iron levels can be seen in patients with pyroluria.
Signs and symptoms of pyroluria
This condition is important to know about because a high incidence of pyrrole disorder is found in individuals with many conditions, including:
- Autism spectrum disorders
- obsessive-compulsive disorder
- bipolar disorder
- alcoholism and addictions
- Multiple sclerosis
- Lyme disease
“As many as 50% of those with autism, 40% of alcoholics, 70% of schizophrenics, 70% of persons with depression and 30% of persons struggling with ADD may have pyroluria underlying these conditions and make them very difficult to reach with traditional and even holistic therapies. –But pyroluria isn’t limited to these populations. As much as 10% of the population may have this metabolic condition and not know it…but may have lifelong symptoms associated with it that tend to worsen with age…and stress.” (http://www.primalbody-primalmind.com/do-you-have-pyroluria/)
In general, the symptoms of pyroluria can have a mysteriously intractable quality to them, and primarily relate to the B6 and/or zinc deficiencies. One source also indicated that accumulated pyrroles can also interfere with the conversion of B6 (pyridoxine) to its active form, pyridoxine-5-phosphate (P5P). The deficiency of P5P can then reduce hemoglobin synthesis, worsening many symptoms. Lower levels of P5P are also associated with lower glutathione levels, which will further increase oxidative stress and decrease detoxification in the body, causing additional symptoms.
I have listed symptoms gathered from a variety of sources and they may include:
- poor stress tolerance
- all symptoms worse with stress
- mood swings or instability
- inner tension
- irritability or emotional reactivity
- episodic anger or aggressiveness
- very sensitive to criticism
- difficulty concentrating
- poor short-term memory
- learning problems, especially with information in written format
- headaches, especially blinding or cluster type
- poor night vision
- poor dream recall
- restless leg syndrome, tingling or tremors
- motion sickness
- sensitivity to light, smell, sound, and/or touch
- frequent or chronic infections
- slow wound healing
- tendency to autoimmune disorders
- muscle weakness
- joint pain or stiffness, especially knee or leg
- hypermobile joints, muscle pain
- gets stitch in the side when running,
especially in children
- hair loss
- premature graying of hair
- white spots on nails
- rough and dry skin
- tendency to acne, eczema, or psoriasis
- being pale, having an inability to tan, or sun burning easily
- irritable bowel syndrome
- gluten intolerance
- difficulty digesting protein and fat
- fat distribution around abdomen
- diarrhea or constipation
- abdominal tenderness
- loss of appetite
- poor sense of taste or smell
- easy bruising/bleeding
- low blood pressure
- cold hands and feet, Raynaud’s syndrome
- spider veins, varicose veins
- heart disease
- higher clotting risk
- tendency to anemia, especially iron deficiency
- fatigue and low energy reserves
- slow growth
- sensitivity to medications
- wide variety of hormonal symptoms or imbalances- thyroid, adrenal, sex hormones
I have also found two slightly different pyroluria symptom questionnaires that may also be helpful at:
One important factor in pyroluria is that the doses of zinc and vitamin B6 required for treatment may be toxic for someone with a normal metabolism. Therefore, testing prior to initiating treatment is important. False negative results are possible and there is a higher incidence of false negative results in children because they have faster metabolisms than adults. Children can still be tested; the practitioner just needs to be aware of potential false negatives and a closely monitored trial of B6 and zinc may still be warranted with a negative result but strong clinical indications. Additionally, because pyroluria is a genetic disorder, other family members should also be tested.
Because pyrroles are excreted in the urine, testing for pyroluria is an easy urine test. Prior B6 and zinc supplements need to be avoided for 24 to 48 hours prior to testing. It is important to choose a lab that corrects for the concentration or dilution level of the sample. Additionally, kryptopyrroles are light sensitive, so the lab should include methods used to prevent the degradation prior to the sample analysis.
Fortunately, pyroluria is manageable with the use of regular supplements, typically high doses of zinc and B6, higher than what can be obtained from food. The type of supplement is important so they can be effectively absorbed; zinc picolinate or gluconate and pyridoxal-5-phsphate (P5P) tend to be the best forms of these nutrients. However, some patients may do best with a combination of P5P and standard B6. Supplementation may need to start at low levels and gradually increase. Supplementation does need to be monitored to avoid toxic levels, as well as ensuring patients are avoiding competing nutrients. For example, copper-rich foods and copper-containing supplements should be avoided because they are antagonistic to zinc.
People with pyroluria also have a higher than normal need for omega-6 fatty acids, particularly arachidonic acid and gamma linolenic acid (GLA). Arachidonic acid is found in eggs, butter, red meat and liver, and GLA is found in supplements like black currant seed oil and evening primrose oil. Other helpful nutrients may include high doses of probiotics; other B vitamins; antioxidants, including glutathione and vitamins A, C, and E; other minerals, including manganese and magnesium; and amino acids, including cysteine, 5-hydroxy tryptophan (5HTP), glutamine, taurine, or glycine. Proteolytic enzymes may be needed to break up accumulated pyrroles. Patients will also need digestive, liver, and brain support as well because the effects of zinc and B6 deficiencies can be wide spread through the body.
Ongoing treatment is required and symptom relapses will occur usually within several weeks of stopping supplementation. Because people with pyroluria have difficulty dealing with the effects of stress, relapses may also occur under different types of mental, emotional, and/or physical stress, including illness, lack of sleep, or injury. However, with proper, continued supplementation, patients with pyroluria can improve their health.
http://www.health-science-spirit.com/pyroluria.htm (Walter Last)
Dr. Renee Schwartz. Seminar: Nutritional Approaches to Treating Pyroluria and Other Depression Biotypes. November 2014.
Methylation is a process where a methyl group (a carbon and three hydrogens) is attached to another substance. Current research estimates that 30 to 40 percent of the population has abnormalities in one or two of the genes for the enzyme methyltetrahydrofolate reductase (MTHFR). This enzyme converts folic acid to 5-methylfolate, which is the active form of folate; abnormalities in this enzyme’s activity can lead to decreased methylfolate production, which can have profound biochemical effects in the body. However, methylation is an extremely complex process involving multiple enzymes and pathways, not just the MTHFR, and abnormalities can occur in other genes/enzymes as well. Abnormalities anywhere in the methylation cycle can result in overall under- or over-methylation, and as such, just testing for this one gene may not show the entire picture of methylation.
Functions of Methylation: Why Should We Care?
The methylation process can affect every cell and process in the human body.
Methylation and acetylation are the two major chemical gene regulators. Not all genes are active at all times and methylation appears to be one of the major methods by which cells lock genes in the “off” position. This is particularly important for turning off cancer genes, but all genes need to have a balance of activity; no gene should be active constantly. Because of this, proper DNA methylation is essential for cell growth and division, and research is indicating links between abnormal methylation with aging, cancer development and progression, and birth defects. Abnormal cell growth can affect any cell that naturally has a rapid turn-over-rate, such as skin, red and white blood cells, and the intestinal lining.
Methylation is required to activate vitamin B12 and folate; without the addition of that methyl group, those vitamins are inactive. If a person has abnormal methylation, the levels of B12 and folate measured in the blood could be normal, but the body could be functioning at a deficiency because those vitamins aren’t in the active form. Vitamin B12 and folate are cofactors in many processes and are essential in red blood cell production and therefore, energy metabolism.
Protein Metabolism and Homocysteine
Methylation is also essential for overall protein metabolism and specifically, the conversion of the amino acid homocysteine to methionine or cysteine. Homocysteine is highly inflammatory and a major and independent risk factor for coronary artery disease and heart disease. Homocysteine levels can be measured in the blood and can be used to evaluate both inflammation levels but also methylation status. Most labs use a reference range that has a normal level just below a cutoff value (e.g., < 15). I evaluate a patient’s result using both upper and lower values to provide a balanced range since either too much or too little methylation may be problematic.
Neurotransmitter Synthesis and BH4 Recycling
Synthesis of neurotransmitters, including serotonin, and dopamine, is dependent on methylfolate, which acts as an enzyme cofactor. If the methylation process is defective, a lower amount of methylfolate may be available, reducing the production of these neurotransmitters.
Methylfolate is also essential for the recycling of tetrahydrobiopterin (BH4), which is an essential cofactor for the production of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine, and epinephrine. BH4 is also required for the production of nitric oxide, which is a strong vasodilator. There is some research that indicates a lack of BH4, and therefore, nitric oxide, may be responsible for circulation-related diseases.
One of the other major roles of methylation is detoxification, as it is one of the major Phase 2 detoxification pathways in the liver. Detoxification occurs in two phases; the first phase occurs by enzymes in the liver cells and it serves to break down a substance so that in Phase 2, another group can be added to it to make it easier for the body to eliminate. There are a number of different phase 2 pathways, and different substances, including hormones, neurotransmitters, and chemicals, are detoxified through different pathways. The challenge in this system lies in the fact that often the product of Phase 1 detoxification is more toxic than the original substance and if there are problems with its Phase 2 pathway, that more toxic substance will remain active in the body for a longer time period.
One particular issue with methylation as a detoxification route is that estrogen is one of the main substances that are detoxified by methylation. Estrogen gets converted to hydroxyl-estrogen via Phase 1, and this form of estrogen is highly toxic, causing DNA damage and contributing to breast cancer risk. Through Phase 2 methylation, that hydroxyl-estrogen is converted to the much less active and safer methyl-estrogen; this form of estrogen actually appears to have some beneficial cardiovascular effects. Understanding the role of methylation becomes exceptionally important in looking at a woman’s estrogen exposure and breast cancer risk, separate from her total estrogen level or her breast cancer genetic status.
Impaired methylation can also decrease glutathione production; glutathione is the primary antioxidant in the human body and one of the major detoxification routes, especially for heavy metals. Methylation is also the breakdown pathway for histamine, and elevated levels of histamine are associated with allergies and brain inflammation. Blood levels of histamine can be evaluated along with homocysteine to give a window into a person’s actual methylation status.
Methyl group donation is essential for the synthesis of carnitine and CoQ10. These two nutrients are required to produce cellular energy in the mitochondria. Without them, the mitochondria cannot produce energy (ATP), which is the biochemical energy source for every process in the body.
Symptoms of Methylation Abnormality
Many different symptoms can be associated with methylation abnormalities, and patients can be overmethylators or undermethylators. Not every patient with a methylation abnormality will have all of these symptoms and some of these symptoms can also be associated with other causes besides methylation. Additionally, there may be overlap between the two patterns.
Symptoms of those two patterns can include:
|Anxiety/ panic attacks||Low pain tolerance|
|ADHD, Hyperactivity, restless legs||Frequent headaches|
|Sleep disorders||Perfectionism, rumination about past|
|Food and chemical sensitivities||Fewer food allergies|
|Lack of respiratory allergies||Environmental/respiratory allergies|
|Dry eyes and mouth||Easy tears, saliva|
|Low libido||High libido|
|Depression but usually worse on SSRIs||Depression better with SSRIs, antihistamines|
Normal methylation and methylfolate levels in particular clearly profoundly affect our health. The question becomes, if a person has one or more of those genetic abnormalities, has evidence of abnormal homocysteine and/or blood histamine levels, and/or has symptoms associated with abnormal methylation, how can we support that process?
There are several supplements we can use to support methylation both directly and indirectly. These include:
- 5 MTHF and methylcobalamin (B12): these may act more directly as enzyme cofactors than methyl donors to the entire methylation cycle.
- Choline, TMG (trimethylglycine or betaine), and DMG (dimethylglycine): Choline is metabolized into TMG, which is involved in SAM(e) synthesis. DMG is formed when TMG loses one of its methyl groups. All three provide sources of methyl groups.
- S-adenosyl methionine [SAM(e)] and methionine: SAM(e) is produced in the liver from the amino acid methionine and is one the best methylating agents available. The challenge is that SAM(e) can be expensive to maintain appropriate dosing levels. Therefore, supplementing with methionine and supporting liver function may be an alternative solution.
Other nutrients that indirectly support methylation and may be considered include zinc, phosphatidylserine, inositol, calcium, magnesium, B complex, and Vitamins B2, B6, A, C, D and E. Glutathione or N-acetylcysteine supplementation may be needed because of the effect methylation has on glutathione production.
It is important to note that some patients who undermethylate do not tolerate methylfolate, especially in high doses. For those patients, other methyl donors may be a better way to support methylation. Additionally, the dose of methyl supports may need to be titrated up slowly to allow for other enzymes time to upregulate. For example, the COMT enzyme breaks down the catecholamine neurotransmitters (serotonin, dopamine, and norepinephrine). If a patient starts a high dose of methyl support and production of those neurotransmitters significantly increases, the COMT enzyme may not be able to keep up with the breakdown, leading to a state of catecholamine excess. Therefore, methylation support may need to be started slowly to reach a relatively high dose to replete deficiencies, and then decreased down to a maintenance level.
Methylation clearly plays a significant role in human health. However, this is definitely one situation where one size does not fit all. Patients need to be evaluated for their methylation status and different methylation supports may need to be used in different doses at different times to support optimal health.
All You Ever Wanted to Know About Thyroid
Thyroid anatomy and physiology
Thyroid gland is a butterfly shaped organ located in front of the throat. The follicular cells of the thyroid gland secrete tetraiodothyronine (T4) and triiodothyronine (T3), which are synthesized by attaching iodine atoms to the amino acid tyrosine. T3 and T4 combine with tyrosine-binding globulin (TBG), a transport protein in the blood, which carries the hormones throughout the body. Approximately 75 percent of the thyroid hormone is bound to TBG, and only the free/unbound portion of the hormone can act in the body.
More than 90 to 95 percent of the hormone the thyroid secretes directly is the inactive form of T4. Under normal circumstances, this T4 then gets converted into four different hormones:
- ~60 percent is converted into active T3 by the removal of one iodine atom by the 5’ deiodinase enzyme and 80 percent of this conversion occurs in the liver;
- ~20 percent is converted into reverse T3 (rT3), which is completely inactive and cannot be reactivated; and
- ~20 percent is converted into T3 sulfate (T3S) and triiodothroacetic acid (T3AC). These are inactive until an enzyme in the intestines converts them into active T3. This process requires healthy intestinal bacteria.
T3 is four times as potent as T4, but lasts a much shorter time. Therefore T4 acts as a reserve for thyroid activity because it can be converted to T3 as needed. There are also specialized cells within the thyroid that secrete calcitonin, which helps regulate calcium levels.
Thyroid hormone secretion is controlled by feedback systems with the pituitary and hypothalamus glands as well as the body’s iodine level. Low levels of T3 and T4 or a lower metabolic rate will trigger the hypothalamus to secrete thyrotropin releasing hormone (TRH). TRH then stimulates the pituitary to secrete thyroid stimulating hormone (TSH), which stimulates the production and release of T3 and T4 from the thyroid gland. So as T3/T4 levels begin to decrease in the body, TRH from the hypothalamus and TSH from the pituitary begin to increase, stimulating the thyroid gland to produce more T4. Production of thyroid hormone will also be stimulated by any situation that increases energy demand, including a cold environment, low blood sugar, pregnancy, and high altitude.
Thyroid functions in body
Thyroid hormones have a wide variety of functions in the body, including:
- regulating the basal metabolic rate to produce energy and heat;
- stimulating protein synthesis;
- enhancing triglyceride breakdown and cholesterol excretion;
- promoting normal growth and development of bone;
- affecting production and function of other hormones, including cortisol, testosterone, estrogen, progesterone, insulin, and growth hormone;
- supporting normal liver and gallbladder function, especially phase 2 detoxification;
- regulating brain inflammation and brain autoimmunity, especially through effects on microglial cells in the brain;
- influencing the actions of and receptors for neurotransmitters, including serotonin, dopamine, GABA, acetylcholine, adrenaline and noradrenaline;
- affecting methylation pathways, and therefore, estrogen metabolism and activity of B12 and folate; and
- accelerating body growth in children, especially in the nervous system.
Symptoms relating to thyroid disorders
Thyroid disorders can be generally divided into low (hypo-) or high (hyper-) thyroid, and in general, hypothyroid conditions are more common than hyperthyroid conditions. Patients with hypothyroid disorders may present with:
- weight gain even with reduced calories due to reduced overall metabolic rate;
- decreased mobilization of free fatty acids from fat tissue;
- slow degradation of lipids;
- delayed insulin response to glucose;
- slow glucose uptake by tissues and decreased glucose absorption in the intestines; and
- slower degradation of insulin, which may present clinically as hypoglycemia.
- morning headaches that wear off through the day;
- bone development delay; and
- muscle cramps and body pain.
- poor brain function;
- depression, and sometimes anxiety; and
- high need for sleep.
- sensitivity to cold/cold weather and poor circulation in extremities;
- low body temperature;
- facial swelling;
- loss of the outer third of the eyebrows;
- difficulty recovering from infections/ healing wounds;
- dry or brittle skin/hair/nails; and
- hair falling out.
- chronic low stomach acid/poor digestion;
- decreased intestinal transit time;
- altered intestinal absorption rates;
- reduced liver clearance with possible AST/ALT elevations on bloodwork;
- sluggish gallbladder contraction;
- abnormal phase II detoxification in the liver;
- decreased B12, folate, and iron absorption; and
- increased intestinal permeability to proteins.
- difficult menstrual periods and/or infertility;
- altered metabolism of androgens and estrogens;
- altered estrogen metabolism toward forms which increases risk for estrogen-related cell growth;
- reduced sensitivity at progesterone receptors (progesterone resistance); and
- increased sex-hormone binding globulin, which affects the free portions of sex hormones.
- atrial fibrillation
There may also be a painless swelling of the thyroid or a sensation of fullness in the throat. Low levels of thyroid hormone can also affect other hormones, such as estrogen or progesterone, which can then cause their own set of symptoms.
Patients with hyperthyroid disorders may present with hypermetabolism, rapid heart rate, and fatigue, weight loss despite normal to increased calories, excess heat, osteoporosis and bone demineralization, nervousness, and tremors.
Testing thyroid and what results mean
There are many tests of thyroid function and it is important to know the information that each of these tests does and does not provide.
- TSH is a direct measure of the amount of TSH produced by the pituitary. Many doctors feel this is best means of determining thyroid dysfunction because they feel normal results essentially rule out hyperthyroidism or hypothyroidism. However, using TSH to evaluate thyroid function doesn’t consider abnormal thyroid-pituitary feedback loops, peripheral thyroid metabolism/conversion issues, or autoimmune thyroid conditions.
- Total T4 (TT4) is a measure of bound and free T4 hormone. Changes in levels of TBG will produce corresponding changes in TT4.
- Free T4 (fT4) is a direct measure of the unbound T4 hormone. This can appear elevated if the TBG levels are decreased.
- Total T3 (TT3) is a measure of bound and free T3 hormone. It tightly bound to TBG (although 10 times less so than T4) and like TT4, TT3 levels are influenced by alterations in serum TBG level and by drugs that affect binding to TBG.
- Free T3 (fT3) is a direct measure of the unbound T3 hormone. This test is usually done to evaluate thyrotoxicosis or when a hyperthyroid patient has normal FT4 levels.
- Reverse T3 (rT3) is a direct measure of the reverse T3 levels. This will be higher primarily under conditions of elevated cortisol and an inability to clear rT3.
- T3 Uptake (T3U) is used to estimate protein binding and measures the number of sites for fT3 to bind with thyroxine binding proteins.
- Free Thyroxine Index (FTI) is a calculated value that corrects TT4 for the effects of varying amounts of thyroid hormone–binding serum proteins and thus gives an estimate of fT4 when TT4 is measured. While it is an older tests, the FTI is readily available and compares well with direct measurement of fT4.
- Thyroid antibodies are measurements of immune activity against different portions of the thyroid. The most common tests are thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies. These tests are used to identify cases where hypothyroidism (Hashimoto’s thyroiditis) or hyperthyroidism (Grave’s disease) is caused by autoimmune activity, and positive results indicate that treatment must be based on treating autoimmunity in addition to appropriate thyroid support.
TPO antibodies target the thyroid peroxidase enzyme, which is important in the synthesis of thyroid hormone inside the thyroid follicular cells. The TPO antibody test is the most sensitive test for detecting any autoimmune thyroid disease and are highest in patients with Hashimoto’s thyroiditis. Tg antibodies bind thyroglobulin, the major thyroid-specific protein that is crucial to thyroid hormone synthesis, storage, and release; these antibodies can interfere with thyroid hormone production. Tg is not released into circulation under normal conditions. However, inflammation, bleeding, or rapid growth of thyroid tumors can cause destruction of the thyroid follicular cells, causing Tg to leak into the blood. This process can cause the formation of Tg antibodies and the exposure of other thyroid proteins to the immune system, especially TPO.
TPO antibodies are positive in 90-100% of cases of Hashimoto’s thyroiditis and 50-80% of cases of Graves’ disease and Tg antibodies are positive in 80-90% of cases of Hashimoto’s thyroiditis and 50-70% of cases of Graves’ disease. TPO and/or Tg antiobdies may also be present in other autoimmune diseases (40% of cases), pregnancy (14% of cases) and sporadic multinodular goiter, isolated thyroid nodule, and thyroid cancer. Elevated levels of TPO or Tg antibodies may be present in 40-50% of relatives of patients with an autoimmune thyroid disorder.
TPO antibody tests are more sensitive than but equally specific to Tg antibody tests for diagnosing autoimmune thyroid conditions. However, for some patients, only the Tg antibodies are positive and anti-Tg levels should be evaluated if TPO antibodies are negative, but clinical suspicion of autoimmune thyroid disease is high. According to the Mayo Clinic, “in patients with subclinical hypothyroidism, the presence of TPO antibodies is associated with an increased risk of developing overt hypothyroidism. Many clinical endocrinologists use the TPO antibody test as a diagnostic tool in deciding whether to treat a patient with subclinical hypothyroidism.”
- Radioactive iodine uptake testing is used to help diagnose hyperthyroidism. A trace amount of radioiodine is given orally or IV and a scanner then detects the amount of radioiodine taken up by the thyroid.
It is important to know that there are medications that can affect both thyroid functioning as well as thyroid test results. Medications can:
- decrease TSH secretion;
- decrease or increase thyroid hormone production;
- decrease T4 absorption;
- increase or decrease TBG, thereby increasing or decreasing the free hormone levels;
- displace T3 and T4 from the transport proteins;
- increase liver metabolism; and
- decrease the 5’deiodinase activity.
Lab Findings with Thyroid Disorders
Lab test results will vary with different types of thyroid disorders.
With hypothyroidism, there will be a high TSH; low-normal TT4, FT4, TT3, FT3, FTI, and T3U; and normal rT3. Antibodies may be negative or positive depending if the cause is autoimmune. If hypothyroidism is caused by low pituitary functioning, the labs will be the same except that the TSH will be low instead of high. In that case, the thyroid itself may be able to function normally, but it is not getting the correct stimulation (TSH) from the pituitary. Other things to consider then include adrenal dysregulation, post-partum, thyroid receptor site resistance, and heavy metal toxicity, all of which will affect pituitary functioning.
Subclinical hypothyroidism occurs when the patient has hypothyroid symptoms and the TSH is mildly elevated but FT4 is within lab reference range; over 80% of patients have a TSH of less than 10 mIU/L. This condition is fairly common and the diagnosis can be supported by positive TPO antibodies. It may be considered a very early stage of an autoimmune condition because the majority of patients diagnosed do go on to develop full hypothyroidism, especially if those patients have positive TPO antibodies.
With hyperthyroidism, there will be a low TSH; high-normal TT4, FT4, TT3, FT3, and FTI; and normal T3U and rT3. Antibodies are almost always positive for hyperthyroidism because almost all cases are due to autoimmunity (Grave’s disease).
Thyroid underconversion is a very common pattern and occurs when the thyroid is producing T4 normally, but the T4 is not being converted to T3 correctly in the body. In this case, labs will show a normal TSH; high-normal TT4, FT4, and FTI; and low t3U, TT3, FT3, and rT3. In this case, current or past causes of downregulation of the 5’deiodinase enzyme need be investigated.
Thyroid overconversion occurs when too much T4 is converted to T3, and the chronic high T3 can lead to thyroid resistance. This is typically caused by elevated testosterone and insulin. In this case, TSH is normal with low-normal TT4, FT4, FTI; high-normal T3U, TT3 and FT3; and normal rT3.
Excess estrogen (e.g., oral contraceptives, hormone replacement therapy, pregnancy) can cause elevations of TBG. In this case, labs will show normal TSH, TT4, TT3, and rT3; low FT4, FT3, and T3U; and low-normal FTI. In this case, patients often do not respond to nutritional thyroid support or thyroid replacement and eliminating exposure to outside estrogens and balancing estrogen levels needs to be considered.
In thyroid resistance, all labs may be within normal ranges or FT4 and FT3 may be elevated. Patients may have no symptoms, or symptoms of either low or high thyroid function. This is may be caused by a fairly rare genetic condition or by functional issues, typically high cortisol, which down-regulates some of the thyroid receptor sites, making them unable to respond to thyroid hormone. For these non-genetic cases, there may also be issues with methylation (high homocysteine), vitamin A deficiency, or insulin resistance.
In Wilson’s syndrome, all lab tests are normal except a persistently elevated rT3 and the patient has hypothyroid symptoms. This is most commonly due to chronically elevated cortisol.
Euthyroid Sick Syndrome most commonly occurs when a patient has another chronic illness that begins to affect the thyroid function test results. The actual results may vary depending on the underlying condition, and for most of these patients, treatment focuses on the underlying illness and thyroid replacement is not recommended.
Autoimmune thyroid conditions can be difficult to assess because antibody levels and their resultant impact on thyroid function can fluctuate depending on factors affecting immune activity. Early cases of Hashimoto’s thyroiditis, patients may present with a high or even normal TSH, hypothyroid and/or hyperthyroid symptoms but no thyroid Abs; in this case there is an autoimmune reaction, but the thyroid tissue has not been attacked enough to cause a change in thyroid test levels. Without intervention, this patient would very likely continue on to develop Hashimoto’s thyroiditis with hypothyroid lab results. For a patient with a low TSH, hyperthyroid symptoms and positive antibodies, it could be Grave’s disease or Hashimoto’s thyroiditis in a hyperthyroid state.
Treatments for Thyroid Disorders
Treatments for thyroid disorders vary greatly and depend on the specific type of imbalance. Thyroid hormone replacement can include synthetic T4 (levothyroxine or synthroid), synthetic T3 (cytomel), synthetic combination (thyrolar) and natural thyroid sources, which include both T4 and T3 (e.g., Armour thyroid, Nature-throid, Westhyroid). Dosing goals should include both achieving optimum lab test results and resolution of patient symptoms.
Thyroid supports include nutrients, herbs, and remedies that support normal thyroid function. These may be helpful in addition to thyroid replacement or in cases where a patient’s lab values are not at optimum, but are still within the laboratory reference ranges. Supports need to be tailored to each patient, and there are some cautions in using thyroid supports. For example, while tyrosine and iodine are necessary to produce T3 and T4, excess levels can be suppressive to thyroid function. If thyroid support is needed, functioning of other hormones should also be addressed.
Autoimmune thyroid conditions require broader treatment to include both support for thyroid function as well as addressing the immune dysfunction, the underlying causes for that dysfunction, and other concurrent health issues. For example, some patients with Hashimoto’s thyroiditis have a defect in the vitamin D receptor which means these patients will require more vitamin D than a “normal” patient. Additionally, patients with Hashimoto’s thyroiditis may also have other concurrent autoimmune conditions, especially celiac disease, and have a higher risk of developing thyroid cancer or pernicious anemia, type I diabetes, or rheumatoid arthritis. It is also important to remember that patients with Hashimoto’s thyroiditis can have periods of episodes of hyperthyroidism if there are periods of greater immune activity and thus increased destruction of thyroid tissue and release of stored thyroid hormone. Autoimmune hyperthyroidism often requires surgical removal or irradiation of the thyroid or pharmaceuticals to significantly suppress thyroid function.
There can also be many other influences on thyroid function, and in some cases, abnormal thyroid labs or thyroid-related symptoms are due to a non-thyroid cause. Thyroid underconversion is most often caused by one or more of the following:
- High cortisol (due to chronic stress, low blood sugar, insulin resistance, anemia, acute or chronic infections, toxicity, surgery, accidents, chronic pain);
- Hepatic dysfunction;
- Imbalances in normal intestinal bacteria;
- Viral infections;
- Low selenium, zinc, and/or iodine;
- Heavy metals;
- Inflammation; and
- Low glutathione.
All of these factors can affect thyroid functioning in general, and any treatment plan needs to investigate these other factors, and provide thyroid support while addressing the underlying cause(s). This will also be true for the hormone imbalances that lead to thyroid overconversion or elevations of TBG. Gluten sensitivity, celiac disease, and gut inflammation can also have a negative effect on thyroid function, as can overconsumption of soy, especially the more highly processed forms. Many of the factors leading to thyroid underconversion may also result in thyroid resistance, and should be investigated when that condition is suspected.
The Merck Manual
Kharrazian, Datis. Functional Blood Chemistry Analysis Seminar.
Thom, Dick. Practical Endocrinology Seminar.
T-helper (Th) cells are classified in a variety of classes, the main ones being designated Th1 and Th2. The balance between these two types of T-helper cells can determine the state of your immune system functions in and impact your overall health.
Th1 cells correlate to the idea of Wei qi, or defensive energy, in Chinese medicine, and promote cell-mediated immunity (CD4 type of T cells, killer T cells (CD8 type), natural killer cells, macrophages). Being in a Th1 dominant immune state directs killer T-cells (CD8) to attack microorganisms and abnormal cells at the sites of infection inside the cells, kills specific fungi, viruses, and bacteria, stimulates natural killer cells and cytotoxic lymphocytes to kill cancer cells. This state is enhanced by several immune communication chemicals, specifically Interluken-2 and 12, and gamma-interferon.
Th2 cells promote humoral immunity (B cells and antibodies) to produce antibodies (e.g., IgG, IgE) to neutralize foreign invaders outside of the cells. This state is enhanced by immune communication chemicals Interleukins 4, 5, 6, and 10, and alpha interferon.
Failure of Th1 and overactive Th2 is found in many chronic diseases, including AIDS, candidiasis, multiple allergies, multiple chemical sensitivities, some autoimmune diseases, viral hepatitis, and cancer. As many serious diseases, such as HIV infection, progess, the immune system shifts from the more effective TH1 state to the ineffective Th2 state.
DIETARY FACTORS THAT SUPPORT Th1
- Omega-3 Fatty acids (DHA/EPA) improve cell-mediated immunity, and reduce Interleuken-6 and triglycerides; found in all cold water fish, especially salmon, sardines, mackerel, halibut, and trout. Fish should be canned, boiled, or broiled instead of fried. Lesser amounts found in dark-green leafy vegetables and sea vegetables (blue green algae, chlorella. (Chlorella also increases cell-mediated immunity by other factors.)
- Oleic acids (monounsaturated) increase IgA antibody (immunity on mucus membranes/ Th3); found in cold-pressed extra virgin olive oil, hazelnut or filbert oil (or the whole nuts), green and ripe olives, and almonds. (Coconut oil neither suppresses nor enhances cell mediated immunity.)
- Vitamin A increases IgA; found in cod liver oil, cooked carrots, squash, pumpkin, and sweet potatoes/yams (any yellow/orange vegetable).
- Vitamin E induces interleuken-2, natural killer cell function, and gamma interferon, and acts as an antioxidant.
- Garlic activates natural killer cells, T-lymphocyte function, and the level of interlueken-2.
- Silica reduces excess IgG, which improves natural killer cell function and improves the integrity of the skin and mucus membranes; found in cooked oatmeal or millet, and the herb horsetail.
- Glutathione acts as an antioxidant and removes toxins from inside cells. It is increased by alpha lipoic acid, selenium, and the amino acids N-acetyl cysteine, L-cysteine, and L-glutamine. Good quality sources of protein can supply many of these amino acids through the diet.
- Proper digestion, including protein digestive enzymes, naturally found in fresh ginger root, raw pineapple, and kiwi fruit. Cayenne before meals stimulates hunger and digestive enzymes. Lemon juice or apple cider vinegar stimulates hydrochloric acid (vinegar also kills HIV). Most of immune system and neurotransmitter receptor sites are in our intestines!
- Healthy balance of intestinal flora increases Interlueken-2 and 12, and gamma interferon production, decreases IgE antibody production (associated with allergic reactions) and all Th2 factors, and increases the anti-tumor activity in macrophages.
- NOTE: One species of intestinal flora promotes Th2, which is streptococcus thermophilus, widely used in the making of commercial yogurt. So if the yogurt contains more thermophilus than acidophilus, there will be more Th2 than Th1!
Sunlight, water, exercise, touch, positive attitude, and acupuncture also increase Th1! Be cautious with echinacea and astragalus because they can increase both Th1 and Th2.
DIETARY FACTORS THAT INCREASE Th2
The three most common factors that increase Th2:
- Faulty digestion, leading to absorption of partially digested and unusable proteins, which increases the antibody immune response to these foreign food particles. This can be improved by proper stomach acid and digestive enzyme function, chewing slowly and eating only when hungry.
- White sugar, which directly weakens the functioning of macrophages, natural killer cells, and other white blood cells, and weakens systemic resistance to all infections.
- Trans-fatty and omega-6 acids, found in most heated and processed vegetable oils (soy, canola, safflower, corn, and sunflower), and the processed foods made from these oils. The trans-fatty acids weaken CD8 killer-T cell activity. Except for expeller pressed oils, nearly all other vegetables are processed with solvents, hexane or gasoline, to remove oils from the seeds. The process also twists the fatty acids out of their normal shape, so when they are incorporated into cell membranes, they produce membranes that are porous and vulnerable to viral infections. The heat, light, and oxygen in the process cause the oils to go rancid.
Other factors that increase Th2 include:
- asbestos, lead, mercury, and other heavy metals, pesticides,
- morphine, tobacco, alcohol, steroids,
- pathogens (including HIV, Hepatitis C, and candida), streptococcus thermophilus,
- continuous stress, negative attitudes and suppressed emotions,
- sedentary lifestyle, lack of water, low body temperature, and chronic insomnia.
Lectures by Satya Ambrose, L.Ac, N.D.
Konlee, Mark. “A Consumer’s Guide to Immune Restoration: The Search for ‘Th1’.” Positive Health News. Report No. 18. Spring 1999.
In Chinese medicine, infections are divided into two main types: wind-heat invasions and wind-cold invasions. Symptoms that help differentiate between the two types include:
|Fever||Light||Can be high|
|Aversion to cold||Pronounced||Slight|
|Headache||Deep, severe||At the back of the head|
|Sweating||None||Slight to profuse|
|Thirst||None or lowered||May be increased|
|Tongue||Body color normal||Red tip or sides of tongue|
The general treatment philosophy for treating a wind-cold invasion is to use warming foods and herbs to cause sweating to open the surface and release the pathogens. For w wind-heat invasion, cooling foods and herbs are used to reduce heat and open the surface.
Eat cool or neutral foods that will cool heat in lung and resolve phlegm. Use mostly liquids (juices, soups, teas) at neutral temperatures (very cold food and drink will weaken the body as they cool it) and maintain fluid intake.
Grains: Millet, barley, wheat, rice, amaranth (especially in soup)
Legumes: Soy, mung beans and sprouts, alfalfa sprouts
Vegetables: Watercress, seaweeds, mushroom, dikon radish, radish, carrot, pumpkin, cabbage, bok choy, cauliflower, white fungus, eggplant, water chestnut, lettuce, summer squash, cucumber, celery, asparagus, Swiss chard, spinach, broccoli, zucchini
Fruits: Apple, banana, Cantaloupe, persimmon, peach, pear, strawberry, citrus, papaya, pomelo, winter melon, watermelon, tomato
Herbs: Chickweed, horehound leaf, nettles, mullein leaf, peppermint, dandelion (greens and root), honeysuckle flowers, lemon balm, cilantro, marjoram
Warming foods: coffee, alcohol, chicken; any foods listed for wind-cold
Wind foods: chicken
Congesting foods: dairy, sugar
Eat warm or neutral foods that will warm the lung and resolve phlegm. Eat food at neutral temperature, avoiding cool or very hot food.
Grains: Oats, spelt, quinoa, sweet brown rice, rice, corn, buckwheat, rye
Legumes: Black beans, aduki beans, lentils
Vegetables: Garlic, green onion, and onion, parsnip, parsley, mustard greens, winter squash, cabbage, kale, leek, chive, peppers (hot peppers in small amounts)
Fruits: Cherry, citrus peel, date
Nuts: Walnut, sunflower seed, sesame seed, pine nut, chestnut
Meat: Beef, lamb
Herbs: Fennel, fenugreek, cayenne, horseradish, fresh ginger, elecampane root, coriander, cinnamon bark or twig, cloves, basil, rosemary, angelica root, dill, anise, caraway, cumin
Cooling foods: raw foods; any foods listed for wind-heat
Wind foods: chicken
Congesting foods: dairy, sugar
* Although coffee and alcohol are warming, they should be avoided as they suppress the immune system.
Cai, J. 2002. Oriental Dietetics Class Notes.NationalCollegeof Naturopathic Medicine. Fall 2002.
Maciocia, Giovanni. 1989. The Foundations of Chinese Medicine. Churchill Livingstone:London.
Pitchford, P. 1993. Healing with Whole Foods: Oriental Traditions and Modern Nutrition. North Atlantic Books:Berkley,CA.
A diet to maintain bone health should focus on adequate, high quality protein and foods high in vitamins and minerals necessary for bone rebuilding.
A vegetarian diet is associated with a lower risk of osteoporosis because animal protein generally contains higher amounts of phosphorous, which mobilizes calcium from bone. Calcium is also mobilized from bone to buffer the acidic breakdown products of protein. However, protein is required to build bone so an adequate amount of high-quality, non-meat protein should be maintained.
- Soy, including tofu, tempeh, soy nuts, miso, fresh edamame beans
- High protein grains (e.g., quinoa)
- Eggs (a complete protein source)
Vitamins and Minerals
A variety of vitamins and minerals are required to support formation and maintenance of healthy bone.
- Vitamin B6
- *Breaks down homocysteine, a protein which promotes osteoporosis, decreases fracture healing time
- Found in: Bran cereals, granola; Watermelon, banana, pineapple; Salmon, rainbow trout, steelhead, mackerel, halibut, tuna, herring; Almonds, sunflower seeds; Tomato, sweet potato, potato, broccoli; Soybeans
- Vitamin C
- *Promotes formation and cross-linking of structural proteins in bone
- Found in: Oranges, grapefruit (and juice), watermelon, cantaloupe, honeydew melon, papaya, kiwi, mango, guava, strawberries, blackberries, blueberries, cherries; Peppers, including red chili, green, sweet; Dark leafy greens, including turnip greens, kale, mustard greens, spinach; Brussel sprouts, cauliflower, broccoli, tomato, sweet potato, cabbage; Mung bean sprouts
- Vitamin D
- *Enhances dietary calcium absorption
- Found in: Vitamin-D fortified dairy products; Fish; Eggs; Liver
- Folic Acid
- *Breaks down homocysteine, a protein which promotes osteoporosis
- Found in: Brewer’s yeast; Blackeyed peas, lentils, lima beans, kidney beans; Peanuts; Turnip greens, Romaine lettuce, dandelion greens, Swiss chard, parsley; Leeks, broccoli, bok choy, acorn squash, tomato, brussel sprouts;Orangejuice; Wild rice, oat bran; Tofu
- Vitamin K
- *Attracts calcium to bone tissue
- Found in: Dark, leafy greens, including kale, collard greens, Romaine lettuce, spinach, Swiss chard; Broccoli, cauliflower, tomatoes, alfalfa; Wheat, oats, rye
- *Reduces urinary excretion of calcium and magnesium
- Found in: Dark, leafy greens, including kale, collard greens, Romaine lettuce, spinach, Swiss chard; Tomato; Pear, apple, prunes, raisins, dates; Peanuts, almonds, filberts; Honey; Seafood
- *Essential in bone formation
- Found in: Dark, leafy greens, including kale, collard greens, Romaine lettuce, spinach, Swiss chard, turnip greens, dandelion greens, beet greens, mustard greens; Sea vegetables, kelp, dulse; Swiss/cheddar/cottage cheeses, goat’s milk, buttermilk, yogurt; Carob flour, dates, figs, raisins; Black-strap molasses; Almonds, brazil nuts, sunflower seeds, sesame seeds, walnuts; Brewer’s yeast; Parsley, watercress, broccoli, celery, rutabaga; Tofu, soybeans; Wheat bran, buckwheat; Olives
- *Inhibits bone resorption
- Found in: Rye, whole wheat, millet; Beans, refried beans; Brazil nuts, cashews, sunflower seeds, almonds, pecans, peanuts; Black strap molasses; Tofu; Prunes, banana; Halibut
- * Influences both matrix and mineral metabolism in bone, and is required for proper calcium metabolism
- Found in: Dark, leafy greens, including kale, collard greens, Romaine lettuce, spinach, Swiss chard, beet greens; Kelp, dulse; Wheat bran and germ, buckwheat, millet, whole wheat, rye;
- Almonds, cashews, Brazil nuts, filberts, peanuts, pecans, walnuts; Molasses; Brewer’s yeast; Tofu; Coconut; Celery, asparagus, cabbage; Bananas, oranges, prunes; Legumes; Nuts, seeds- cashews, almonds
- *Increases amount of calcium laid down in bone
- Found in: Dark, leafy greens, including kale, collard greens, Romaine lettuce, spinach, Swiss chard; Celery, beets, asparagus; Bran, whole grains; Pineapple, banana; Egg yolks; Legumes
- *Reduces urinary excretion of calcium
- Found in: banana, raisins; Potatoes; Salmon, halibut; Carrots; Almonds; Soybeans
- *Essential for bone formation and enhances vitamin D action
- Found in: Wheat germ; Pumpkin seeds, sunflower seeds; Seafood; Nutritional yeast; Soybeans
Additional lifestyle changes, such as weight bearing exercise, and supplementation for hormone balance or additional nutritional needs should be addressed with dietary changes. Any organ system imbalance and energetic patterns underlying the development of osteoporosis also need to be treated.
- Refined sugar
- Processed foods
- High sodium, high fat
- Soda (any high phosphorous beverages)
In Chinese medicine, osteoporosis may be associated with yin deficiency and/or liver blood and/or yin deficiency.
Foods that tonify yin
- Millet, barley, wheat germ, wheat, teff, quinoa, amaranth
- Seaweeds, algae
- Black beans, kidney beans, mung beans and sprouts
- Beets, string beans
- Persimmon, grapes, blackberry, raspberry, mulberry, banana, watermelon
- Dairy, egg
Foods that build liver blood and yin
- Mung beans and sprouts
- Chlorophyll-rich foods
- Flax, borage, evening primrose oils
- Grapes, huckleberry, blackberry, raspberry
- Black strap molasses
Hudson, T. 1999. Women’s Encyclopedia of Natural Medicine. Keats Publishing:Los Angeles,CA.
Marz, R. 1999. Medical Nutrition from Marz, 2nd Edition. Omni-Press:Portland,OR.
NationalCollegeof Naturopathic Medicine. Dietary Guidelines for the Prevention of Osteoporosis.. Patient Handout.Portland,OR.
Pitchford, P. 1993. Healing with Whole Foods: Oriental Traditions and Modern Nutrition. North Atlantic Books:Berkeley,CA.