PREDICTIVE AUTOANTIBODIES—YOU MAY HAVE AN AUTOIMMUNE DISEASE AND NOT KNOW IT!

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Any disease condition is a continuum. This means that you do not move from being well to having a disease overnight. Just as in Type 2 Diabetes, where you may have dysregulated blood sugar levels (Dysglycemia) many years before you develop the disease, so it is with many autoimmune conditions. You may have autoantibodies in your blood many years before developing the disease. Despite recent advances in treatment, there is a large percentage of people in whom long-term remission of the autoimmune disease cannot be achieved. This leads to poor quality of life and sometimes an early death. As this oft-quoted Benjamin Franklin axiom says “an ounce of prevention is worth a pound of cure”. Several scientific studies in the last few years have shown that you may have tell-tale evidence in your body 5-14 years before developing an autoimmune disease. An autoimmune condition develops when there is an interaction between your genes, an environmental trigger, your immune system and intestinal permeability. Your genes are present from birth but you do not develop an autoimmune disease until later. So what happens? In any autoimmune disease like it is in any other disease, it is an interaction between your genes and the environment that decides your health. As Dr. Eric Topol, a world-renowned cardiologist, geneticist, digital health pioneer, and medical innovator, says,“healthy aging is 100 percent due to genetics and 100 percent due to your environment”.

Autoimmune conditions develop when your immune system makes antibodies against your own tissue ( Autoimmunity).  This can lead to your healthy tissue losing their ability to function normally. For example, in Type 1 Diabetes, your own body makes antibodies against your own pancreatic cells which produce insulin. Insulin is the hormone that keeps your blood sugar in balance. The other, commoner diabetes is Type 2 Diabetes, in which antibodies to pancreatic tissue is not usually present. (Incidentally, these autoantibodies to pancreatic tissue have been found in about 5% of people otherwise diagnosed as Type 2 Diabetes.Watch for post on LADA , Latent Autoimmune Diabetes of the Adult).

In fact, a new staging approach is being used in Type 1 Diabetes taking into consideration the number of autoantibodies present. The staging starts well before the disease develops. This approach is used to prevent or delay the onset of the disease. Perhaps you can start prevention in your child when you are pregnant! Studies have shown the connection between vitamin D deficiency in mothers and autoimmunity in children.

Rheumatoid Arthritis (RA): RA is an autoimmune disease affecting joints, which is characterized by chronic inflammation, causing pain and stiffness in the joints and a poor quality of life. Half of the patients with RA already have X-ray evidence of joint damage at the time of diagnosis. Like most diseases, RA can be treated better if diagnosed early. Therefore, the ability to predict the disease before joint damage occurs will contribute to a better quality of life.

WHO SHOULD BE TESTED FOR AUTOANTIBODIES?

  • Anyone who has a diagnosed autoimmune condition. Studies have shown that if you have one autoimmune disease, the chances of your developing another one are much higher than in the general population.
  • To test for disease progression in people with autoimmune diseases.
  • Anyone with hypothyroidism who has never been tested for thyroid antibodies.
  • First degree relatives (a person’s parent, sibling or child) of people with an autoimmune condition.
  • Patients with painful and stiff joints who haven’t received a definitive diagnosis of RA yet.
  • Anyone interested in better health.

WHAT TESTS SHOULD YOU DO?

A complete workup is very important. However, the following must be included.

  • C-Reactive Protein: This is a marker of inflammation.
  • Vitamin D3 levels: Vitamin D has a major role in your immune system. Low levels of this vitamin have been associated with increased risk of autoimmune diseases. (Vitamin D)
  • Antibodies: This list increases by the day. There are some specialized tests available in some countries which I have not listed here. (For those of you interested in the detailed medical information, please read the article in Autoimmunity reviews6 (2015) Damoiseaux, Jan, et al.).

This table has a short list:

                      ANTIBODY              AUTOIMMUNE CONDITION
ANA Lupus, Scleroderma, Autoimmune Hepatitis, Sjogren’s Disease, Polymyositis, Dermatomyositis, Mixed Connective Tissue Disease, Juvenile Arthritis, Drug-induced Lupus.
Anti-Cyclic Citrullinated Peptide (Anti CCP) Rheumatoid Arthritis
Anti TPO & Anti Thyroglobulin Hashimoto’s Thyroiditis
Anti TSH Receptor Graves’ Disease
Anti-tissue transglutaminase (tTG) antibodies

Endomysial antibodies (EMA)

Deamidated gliadin peptide (DGP) antibodies

(IgA & IgG tests)

Celiac Disease

 

 

Islet Cell Cytoplasmic Autoantibodies (ICA) & Glutamic Acid Decarboxylase Autoantibodies (GADA) Type 1 Diabetes, Late Autoimmune Diabetes of the Adult(LADA).

WHAT IS THE DIFFERENT ABOUT THE FUNCTIONAL AND METABOLIC MEDICINE APPROACH?

Fig 1: Functional & Metabolic Medicine approach versus Conventional Approach:Fork in the road.

Slide1
Fig 1

WHAT SHOULD YOU DO?

  • Meet a practitioner who understands the Functional & Metabolic Medicine approach to autoimmunity. There are no pharmaceutical drugs that can be used to prevent autoimmune diseases before they develop.
  • Stop smoking (Easier said than done!). Exposure to cigarette smoke has been associated with higher risk of Rheumatoid Arthritis in those susceptible to it.
  • Reduce toxic exposure.
  • Reduce inflammation.
  • Manage stress.
  • Maintain adequate Vitamin D3 levels (Vitamin D)

REFERENCES

  • Avouac, Jérôme, Laure Gossec, and Maxime Dougados. “Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review.” Annals of the rheumatic diseases7 (2006): 845-851.
  • Catrina, Anca I., et al. “Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis.” Nature Reviews Rheumatology 11 (2014): 645-653.
  • Damoiseaux, Jan, et al. “Autoantibodies 2015: From diagnostic biomarkers toward prediction, prognosis and prevention.” Autoimmunity reviews6 (2015): 555-563.
  • Nielen, Markus MJ, et al. “Increased levels of C‐reactive protein in serum from blood donors before the onset of rheumatoid arthritis.” Arthritis & Rheumatism 8 (2004): 2423-2427.
  • Notkins, Abner Louis. “New predictors of disease.” Scientific American3 (2007): 72-79.

VITAMIN D AND AUTOIMMUNITY

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In recent years vitamin D deficiency has become like an epidemic all over the world. Besides autoimmunity, low vitamin D is associated with many diseases like heart disease, diabetes, cancer, hypothyroidism and many more. In fact, almost every cell in your body has vitamin D receptors.

There are 2 forms of vitamin D3 that you need to keep in mind. The one that is usually tested by most practitioners is Vitamin D3. Your body has to convert Vitamin D3 to the active form 1,25 Dihydroxyvitamin D3[1,25(OH)2 D3]. Most of you are familiar with the action of vitamin D in protecting your bones and maintaining blood calcium levels—the “classical” actions of vitamin However, scientific studies in the last several years have shown that vitamin D has several other actions as well—the “non-classical” actions. These are the actions of vitamin D on bone marrow, immune system, breasts, prostate, heart, muscles and intestine. With respect to autoimmune disease, the immunomodulatory (affecting your immune system) actions of Vitamin D are very important.

Vitamin D has the effect of increasing the activity of the innate immune system while restraining the activity of the adaptive immune system. (Chapter 9). This is the reason why adequate vitamin D3 levels are important for treating and perhaps preventing autoimmune diseases. A substantial number of studies have shown an association between low vitamin D and increased incidence of autoimmune diseases like Rheumatoid Arthritis(RA), Multiple Sclerosis(MS), Psoriasis, Inflammatory Bowel Disease (IBD), Type 1 Diabetes, Sjogrens, Lupus and many more. One example that is often cited is the increasing incidence of MS as one moves away from the equator. This is thought to be related to lesser sun exposure at higher latitudes than at the equator.

1,25 DIHYDROXYVITAMIN D3.

In autoimmune conditions sometimes measuring only vitamin D3 levels may not be enough. A few scientific studies have shown that some people with autoimmune disease have high levels of 1,25 Dihydroxyvitamin D3. This is why sometimes we need to measure both the forms of vitamin D. I remember quite a few occasions when my patients (In India) have called me to say that the lab technician has informed them that “no doctor advises this (1,25 OH)2 D) test” so it is unnecessary!

WHY DO PEOPLE BECOME VITAMIN D DEFICIENT?

Humans obtain vitamin D from either food (fortified), supplements or sunlight exposure. Your blood vitamin D levels depend on several factors.

Air quality: Excessive carbon particles in air from burning of fossil fuels may reduce the amount of vitamin D producing UVB rays from reaching your exposed skin.

Skin color: People with dark skin require about 10 fold more exposure to sunlight to produce the same amount of vitamin D as people with lighter skin color.

How much of your skin is exposed? The more bare skin the bigger the surface area of absorption of sunlight.

Use of sunscreens: Though theoretically use of sun screens can block the UVB rays, rarely do people use adequate quantities of sunscreen to bar all UVB from reaching their skin.

Gut Health: If you have unhealthy gut or you have inflammatory bowel disease (IBD), your absorption of vitamin D from supplements is poor.

Liver and Kidney Health: Some types of liver disease may affect bile production. This can affect vitamin D function. In chronic kidney disease (CKD) the vital step of conversion of vitamin D to its active form is affected and this can lead to severe vitamin D deficiency. This is why patients with CKD have their 1,25 Dihydroxyvitamin D3 measured regularly.

Vitamin D receptor (VDR): If you have a genetic variation in VDR you may need a higher dose of vitamin D supplementation.

How much vitamin D3 you take will decide your blood levels of the vitamin. Very low or very high doses, may both be detrimental unless you monitor regularly.

HOW MUCH VITAMIN D SHOULD YOU TAKE AS A SUPPLEMENT?

How much supplementation of vitamin D you need depends on what your blood reports show. It may not be the same dose for everyone because of individual variations. However, it is a much better idea to take a smaller dose (4000-5000 IU) every day rather than a very high dose once a week or once a month. Sometimes a larger dose may be necessary for a short period of time until your blood levels are in the optimal range.

Ideally you should get your vitamin D from sensible sun exposure AND supplementation.

 WHAT IS MOST IMPORTANT ABOUT VITAMIN D AND AUTOIMMUNE CONDITIONS?

Low vitamin D levels have been associated with many autoimmune conditions like

Rheumatoid Arthritis (RA), Multiple Sclerosis(MS), Psoriasis, Inflammatory Bowel Disease (IBD), Type 1 Diabetes, Sjogrens, Lupus and many more. This is because vitamin D affects your immune system function.

Maintaining adequate vitamin D levels may be a major way to prevent developing autoimmune disease. In fact, studies have shown that maintaining adequate vitamin D levels during childhood can prevent the development of Type 1 Diabetes by 29%! This is true for several other autoimmune conditions as well.

If you already have an autoimmune condition maintaining adequate vitamin D levels will make a major difference to how you heal the disease.

Some of you  may need to measure both vitamin D3 and 1,25 Dihydroxyvitamin D3.

DO YOU KNOW IF YOU HAVE HASHIMOTO’S THYROIDITIS?

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THYROID OVERVIEW

The thyroid gland is a butterfly shaped gland situated at the base of the neck. It is a part of a large network of glands comprising the endocrine system. The thyroid gland produces hormones that regulate metabolism, growth and development. Thyroid diseases occur when the gland produces either too little hormone (hypothyroidism) or too much hormone (hyperthyroidism).

The most common thyroid diseases are:

  • Hashimoto’s Thyroiditis
  • Grave’s Disease
  • Goiter
  • Thyroid Nodules

Hashimoto’s Thyroiditis (HT) and Graves’ Disease (GD) are Autoimmune Thyroid Disorders (AITD). Autoimmune conditions develop when your own immune system considers your own tissue as harmful foreign invaders that need to be destroyed.

HASHIMOTO’S THYROIDITIS

This is also known as chronic lymphatic thyroiditis and is the commonest cause of hypothyroidism worldwide. Some of you may have it but not know it because, you have not been tested for Thyroid Antibodies. A regular thyroid test done by most practitioners does not include an Anti TPO or Antithyroglobulin Antibody (Anti TG) test. The main reason being that in conventional medicine there is nothing much that can be done to reduce the antibodies apart from prescribing Levothyroxine (Synthroid/Eltroxin/Thyronorm). However, this is where the Functional and Metabolic Medicine approach differs. We know that when we address gut health, nutrient depletions, your HPA Axis dysfunction (Dysregulated Stress response), reduce toxic exposure, maintain adequate Vitamin D3 and help you make lifestyle changes, antibodies to many autoimmune conditions either reduce or disappear. Am I suggesting that you should stop your thyroid medications? Definitely not! However, the amount of medication that you need may be less. Some of you will still need lifelong thyroid medication if your immune system has destroyed most of your normal tissue or you have been diagnosed late.

Symptoms of hypothyroidism:

  • Fatigue
  • Weight gain
  • Depression
  • Anemia
  • Cold feet & palms
  • High cholesterol
  • Lack of motivation
  • Slow movements
  • Hoarse voice
  • Loss of libido
  • Ringing of the ears
  • Hair loss
  • Palpitations
  • Breathlessness
  • Intolerance to heat or cold
  • Carpal Tunnel syndrome
  • Loss of outer third of eyebrow
  • Memory loss
  • Poor concentration
  • Loss of drive
  • Mood swings
  • Irregular menstruation
  • Infertility
  • Constipation
  • Goiter (enlarged thyroid)

THYROID HORMONE SYNTHESIS

The two most important hormones produced by the thyroid gland are tetraiodothyronine (thyroxine or T4) and triiodothyronine (T3).

HYPOTHALAMIC-PITUITARY-THYROID (HPT) AXIS 

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As shown in the picture, the thyroid gland is influenced by two other hormones.

  • Thyroid Releasing Hormone (TRH) from the hypothalamus in the brain and
  • Thyroid Stimulating Hormone (TSH) from the pituitary gland, located at the base of the brain.

The hypothalamus, pituitary and thyroid glands along with the hormones they produce are together called the Hypothalamic-Pituitary-Thyroid (HPT) Axis. The thyroid gland produces T4 and some T3. The more active form of the hormone is T3. The conversion of T4 to T3 happens mostly in liver, kidneys and brain. Most of the thyroid hormones are bound to thyroid binding globulin (TBG). It is the unbound form of the hormones, the Free T3 and Free T4 that are important for thyroid hormone actions. This is why measuring only TSH, Total T3 & Total T4 do not provide an accurate picture of thyroid function.

If thyroid hormone levels are low in the blood, the hypothalamus and pituitary detect this.TRH released from the hypothalamus stimulates the pituitary to produce TSH, which in turn acts on the thyroid gland to produce thyroid hormones.TSH levels can go up if adequate thyroid hormones are not produced as a result of autoimmune destruction of thyroid tissue or because of nutritional deficiencies, like iodine deficiency.

There are few enzymes called deiodinases which are important for activation and inactivation of T4. One of them called the DIO2 (Type2 Deiodinase), which is present in the brain, is very important for thyroid hormone actions. This is relevant in thyroid hormone replacement (Ref Chapter 7).

FUNCTIONS OF THYROID HORMONES:

It is likely that every cell in the body is a target for thyroid hormones. The most important functions are:

Lipid Metabolism: Thyroid hormones are important for lipid metabolism. This is the reason for raised cholesterol and triglyceride levels when your thyroid function is deficient. Thyroid hormones are also important for carbohydrate metabolism.

Brain Development in the fetus is dependent on the mother’s thyroid function. This is the reason for checking thyroid function before contemplating a pregnancy. Normal thyroid hormone levels are also important for normal development of children.

Reproduction: Thyroid dysfunction can lead to infertility in some people.

Cardiovascular System: Thyroid hormones increase heart rate, contractility and cardiac output.

Central Nervous System: Thyroid hormones are intimately associated with mental state. In fact, about 20 % of people with depression may have undiagnosed hypothyroidism.

FACTORS AFFECTING THYROID FUNCTION

  • Iodine
  • Iron
  • Zinc
  • Selenium Vitamins A, B complex, C, D& E
  • Tyrosine
  • Stress
  • Inflammation
  • Drugs like lithium, amiodarone.
  • Heavy metal toxicities
  • Pesticides
  • Exposure to Endocrine Disruptors like Bisphenol-A
  • Infections
  • Trauma

THYROID FUNCTION TESTS:

Below is a list of thyroid function tests. All the tests may not be necessary for all of you. However, this is a decision to be made by you in consultation with a knowledgeable doctor.

  • TSH
  • Free & Total T3
  • Free & Total T4
  • Anti TPO & Anti Thyroglobulin Antibody (For Hashimoto’s Thyroiditis)
  • Anti-TSH receptor Antibody (For Graves’ Disease)
  • Thyroglobulin
  • Thyroid Binding Globulin
  • rT3
  • Tests for nutrient depletions like Iron,vitamin D3, Selenium,Zinc, Iodine etc.
  • Tests for heavy metal toxicities

TRH is usually not tested for because the TSH test is sufficiently sensitive.

TREATMENT : Please check my previous post:http://www.betterforlife.in/blog/2016/05/thyroid-hormone-replacement-only-t4-or-a-combination-of-t3-and-t4/

ACTION STEPS:

  1. Get the right tests done. If you have not been tested for thyroid antibodies, you DO NOT KNOW whether you have Hashimoto’s Thyroiditis (Autoimmune Thyroid Disease)
  2. Do not stop or reduce your thyroid medications without discussion with a knowledgeable doctor.
  3. Maintain adequate Vitamin D3 levels
  4. Check for nutrient depletion.
  5. Maintain good gut health.
  6. Look for anemia.
  7. Reduce your toxic burden
  8. Address your dysregulated stress response.

 

 

 

 

 

THYROID HORMONE REPLACEMENT-ONLY T4 OR A COMBINATION OF T3 AND T4?

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Hypothyroidism is a condition where your thyroid gland produces insufficient amounts of thyroid hormone. The most common cause of hypothyroidism is an autoimmune condition called Hashimoto’s Thyroiditis, where your body’s own immune system attempts to destroy your thyroid tissue.

WHAT IS THE BEST TREATMENT FOR HYPOTHYROIDISM?

  • Is it Levothyroxine T4 (Synthetic T4, Synthroid, Thyronorm, Eltroxin)?
  • Is it a combination of T4 and T3 (Levothyroxine and Cytomel)?
  • Is it compounded bioidentical combined T4 and T3?
  • Or is it thyroid glandular extracts?

The truth is there is no one right answer! It depends on what works for you!

LEVOTHYROXINE (T4) MONOTHERAPY

Using Levothyroxine to replace thyroid hormone in hypothyroidism is the standard of care all over the world. This is the view endorsed by major thyroid and endocrine associations worldwide. However, many people on synthetic T4 alone have not felt their best despite progressively increasing their T4 dosage. This can happen because of several reasons, some of them being low iron storage, poor gut health causing improper absorption of T4 or wrong time of taking T4 in relation to meals. For optimal T4 absorption, you should not take any food or supplements one hour before and one hour after taking T4. In such people who still experience fatigue, weight gain and “brain fog” and their test reports are in the” normal” range, while on T4 only, what should the doctor do? Should you consider a combination of T4 and T3? I get a lot of my patients at this point, when their regular doctor has decided that they need an anti-depressant in addition to T4 or even worse, they are told it is “all in their head” (ironically this may not be far from the truth when we consider the Type 2 Deiodinase(DIO2) enzyme in the brain! More on this later).

COMBINATION THERAPY WITH T4 AND T3 (T4/T3)

Triiodothyronine (T3) is the more active form of thyroid hormone. Your thyroid gland produces T4 and a small quality of T3. Most of the T3 in the blood comes from conversion of T4 in tissues like liver, kidneys and brain. This conversion happens through the action of certain enzymes called Deiodinases. Several studies in the past few years have suggested that in some patients, treatment with combined T4/T3 instead of monotherapy with T4 may show better results, particularly in terms of psychological well-being. Why is this so? One of the possible explanations could be a genetic variation in the DIO2 (Type 2 Deiodinase) gene, which affects the conversion of T4 to T3 in the brain. This DIO2 gene variation does not affect blood levels of thyroid hormones. So your blood levels of thyroid hormones may remain in the normal range, but you don’t feel well. However, this genetic test is not routinely available yet, other than in research settings. So what should you do? A trial of combined T4/T3 is definitely a worthwhile option.

What combinations of T4/T3 are available?

1) Synthetic T4 and Cytomel (T3)

2) Compounded combined T4/T3

Which should you choose? Depends on many variables. But as always, adequate knowledge in their use is extremely important.

WHAT ABOUT THYROID GLANDULAR EXTRACTS?

Thyroid glandular extracts are prepared from thyroid glands of pigs. Armour Thyroid and Naturethyroid are the common ones. It is a combination of T4 and T3 and on US Pharmacopeia, which means that it has standardized dosage of T4 and T3. Use of thyroid glandular extracts sometimes becomes an emotional issue, with one camp being all in favor of it and another completely against it.

One crossover study of 70 patients by Hoang et al in The Journal of Clinical Endocrinology & Metabolism (2013) found that people on Armour Thyroid felt better and about 48% of them preferred Armour over T4 mono therapy. There were no adverse effects on thyroid glandular extracts. However, one major question that this study did not answer was whether there was any change in thyroid antibody levels when on porcine glandular extracts. The study did not measure thyroid antibodies in the patients. Many of us in Functional Medicine do not recommend porcine glandular extracts in patients with positive thyroid antibodies because of the risk of increased autoimmunity from an animal protein.

Sometimes we forget how far we have come in Medicine. George R Murray’s account “The life-history of the first case of myxedema treated by thyroid extract” in BMJ 1920 reads like a beautiful story.Dr. Murray mentions that Dr. Michell Clarke in 1892 had failed to find success in using thyroid glandular extracts because his butcher had been providing him with thymus instead of thyroid glands to make glandular extracts! At least we don’t have to depend on our butcher!

 

For Readers in India: 

As far as I know Cytomel (T3) is not available in India. Compounded combined T4/T3 is not easily available either. More importantly, thyroid hormone is not easy to compound so quality control in the compounding pharmacy is very important. Moreover, compounded hormones are more expensive than the synthetic T4 (Thyronorm, Eltroxin). Thyroid glandular extracts are made from pig thyroid glands and not available in India.

You may be interested in Autoimmunity

REFERENCES:

Murray, George R. “The life-history of the first case of myxedema treated by thyroid extract.” British medical journal 1.3089 (1920): 359.

Panicker, Vijay, et al. “Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients.” The Journal of Clinical Endocrinology & Metabolism 94.5 (2009): 1623-1629.

Hoang, Thanh D., et al. “Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study.” The Journal of Clinical Endocrinology & Metabolism 98.5 (2013): 1982-1990.

Pepper, Gary M., and Paul Y. Casanova-Romero. “Conversion to Armour thyroid from levothyroxine improved patient satisfaction in the treatment of hypothyroidism.” Journal of Endocrinology, Diabetes & Obesity 2 (2014): 1055-1060.

Wiersinga, Wilmar M. “Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism.” Nature Reviews Endocrinology 10.3 (2014): 164-174.

Schmidt, Ulla, et al. “Peripheral markers of thyroid function: the effect of T4 monotherapy vs T4/T3 combination therapy in hypothyroid subjects in a randomized crossover study.” Endocrine Connections 2.1 (2013): 55-60.