Beyond TSH – additional markers for hypothyroidism -additional conversations with your doctor

Remember to smile and be nice when talking with your Dr.

When I completed my master’s degree in endocrinology I put some effort into demonstrating the pitfalls of evaluating thyroid function via thyroid stimulating hormone and the thyroid hormones. It was useful to show how the somewhat crude but helpful variables of body temperature (Tb) and heart rate (Hr) can indicate a low metabolic state. It got me thinking about all the other useful potential markers of metabolic decline associated with hypothyroidism or a functionally hypothyroid state that a person could request to back up the suggestions of low thyroid function.

First, it’s useful to clarify where an individual is at with aspects of Tb and Hr. I had a client who came back to me extremely annoyed because her doctor had laughed at her using a thermometer to establish metabolic function, yet the end result was that she was put on thyroid hormone. Understanding whether you as an individual or your client is in a sympathetic, compensatory state is essential to determining compensated versus actual Tb and Hr. In a compensatory state of low thyroid availability, assimilation or utilisation the body will increase adrenaline, noradrenaline and cortisol as a temporary response to maintain homeostasis (Peat, 1999) (Fommei & Iervasi, 2002). If you’re eating well, consuming little anti-metabolic foods and eating on a regular basis this may not be the case and a functionally hypothyroid state can probably be ruled out. However long term subclinical or undetectable hypothyroidism will often go through a compensatory stage recruiting sympathetic hormones to maintain function.

As thyroid hormone permeates every level of function, it’s useful to consider some of the systemic mechanisms that thyroid affects so that single use medications can be avoided.

Blood glucose – increased then decreased in hypothyroidism

Blood pressure - decreased then increased in hypothyroidism

Cholesterol values - increased in hypothyroidism

Energy production – decreased in hypothyroidism

Digestion decreased function then after chronic damage increased evacuation

Fertility – decreased in hypothyroidism

Heart rate – decreased in hypothyroidism but dependent on compensation

Ovulation – decreased in hypothyroidism

Tendon reflexes – decreased in hypothyroidism

Systemic diseases tend to not spring up in isolation. Acquired inheritance, phenotype expressions, environmental stimulus and nutrition are just some of the factors that allow different losses of function to appear first, it’s never a neat and tidy ordered response with disorder. For some it might be blood pressure, in other cholesterol elevation or digestive disturbances.

Albumin

Albumin Is a major blood protein that’s responsible for 80% of the colloid osmotic pressure between blood and tissue fluids and can also transport thyroid hormones. During states of hypothyroidism albumin metabolism is reduced an may often present with hyperalbuminemia. Hypothyroidism and combinations of excess estrogens often induce vascular leakage of albumin and this can also show up in an individual’s urine.

pH balance and your toilet.

Bicarbonate Typically hypothyroid people can hyperventilate which increases the wastage of carbon dioxide. Bicarbonate is the alkaline ion that is converted via carbonic anhydrase to CO2 when regulating cellular pH levels . To acidic and carbon dioxide is expelled from the body, if chronic the base ion bicarbonate is converted and lost and therefore low levels of bicarbonate are a common finding of hyperventilation and a respiratory alkalosis can ensue to compensate for CO2 loss. From a blood pH perspective as carbon dioxide increases this facilitates the Bohr effect, increasing acidity and allowing respiration to occur via release of oxygen from haemoglobin. As pH is restored to 7.4 or elevates beyond, an alkalosis can occur, decreasing respiration rate and attempts to retain CO2.It’s useful to think of the balance between bicarbonate and CO2 through evacuating functions. During vomiting hydrogen ions are lost and increased bicarbonate ratio. During diarrhoea bicarbonate ions are lost increasing hydrogen and acidosis.

Blood pressure Hypothyroidism is well known to exert negative cardiometabolic effects that extend to decreased blood volume, increased mean arterial pressure MAP, increased ST segment of ECG (electrocardiogram) and arterial stiffness. Hypertension is usually diagnosed at 140/90 mm/HG A simple blood pressure measurement can be useful combined with any of the discussed markers.

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Cholesterol – Broda Barnes presented the notion that elevated LDL cholesterol values were a classic sign of hypothyroidism (Barnes, 1942), yet still many people are often prescribed statins due to poor evaluation of thyroid function. LDL receptors and liver regulation of cholesterol are reduced in hypothyroidism. The previous data on cholesterol values have shown vast differences on optimal LDL values and ranges these days are to suit financial criteria rather than lifesaving values. In neuro degenerative diseases those with higher cholesterol values generally have more positive outcomes than lower.

Iron You may have been told that you have low iron based upon some basic iron/ferritin blood tests and told to take additional iron. Feel better temporarily then present with constipation and more fatigue. Chances are you may have low thyroid function. There can be many reasons why you present with a low serum iron and these can include vitamin A deficiency, low thyroid and a stressed tissue response often called the CDR or Cell danger response. An iron test even with an RBC can be of little relevance. Many females are often misinformed that the menstrual cycle correlates with increased iron needs. The about of menstrual flow doesn’t appear to correlate with iron loss and most deficits can be maintained by red meat and an increased uptake facilitator like vitamin c. Often if experiencing an infection or illness a requirement of vitamin A is necessary to increase iron status.

In order to adequately assess iron need additional test of ferritin, Total iron binding capacity (TIBC) and % transferrin saturation are necessary. It’s often rare that the anaemic states that everyone reports are related to an actual iron deficit. In overt states of hypothyroidism low levels of iron and ferritin are usual whereas TIBC is often elevated (Dahiya et al., 2016). This may be a useful tool in assessing a subclinical or undetectable state of hypothyroidism from regular thyroid biochemistry. Anaemia in many forms is a product of low thyroid function.

Prolactin – Produced by the pituitary, usually from stimulation from the hypothalamus, decreased dopamine allows prolactin (PRL) stimulation. Equally an excess of estrogen stimulates both prolactin and TRH. Estrogen is well known to suppress thyroid hormone conversion and therefore PRL can be a useful reflection of estrogen stimulation of the lactotrophs, which secrete PRL. Those with hypothyroidism generally produce more PRL are associated with hyperprolactinemia and heart disease (Binita, Suprava, Mainak, Koner, & Alpana, 2009)(Reuwer et al., 2009)

Red blood cell count A variety of studies provide differing views on total red blood cell indices but a pattern found in hypothyroidism is decreased Red blood cell count (RBC), haemoglobin (H) and haematocrit (HCT). However increased red distribution width (RDW) correlates with increasing TSH. Increased RDW is often found elevated in cardiovascular disease (a well -known factor negated by Barnes's original studies), and associated with a poorer outcome (Danese, Lippi, & Montagnana, 2015). As this also seems to increase during subclinical hypothyroidism RDW increases and decreasing RBC count might be a useful observation.

Sex Hormone Binding Globulin – SHBG is a protein that has been suggested as a useful marker for diagnosing peripheral resistance of thyroid hormone. This in itself is supposed to be quite rare but I generally think that increased rates of pollution will ultimately affect peripheral resistance not just by modulation of thyroid hormone and estrogen receptors (THR and ER) but conversion and transport. Optimal thyroid regulation is regulated by the deiodinase enzymes which also have an effect on monocarboxylate transporters 8 and 10 (MCT 8 and MCT 10. MCT 8 regulates thyroid hormone transfer to the nucleus of the cell.

All of the above mentioned factors appear to be negatively affected by pollution such as polyaromatic hydrocarbons and many others (Annamalai & Namasivayam, 2015) (Oliveira, Chiamolera, Giannocco, Pazos-Moura, & Ortiga-Carvalho, 2018). Decreased SHBG (and failure to increase with additional TH) can be a marker of a peripheral resistance if THs are elevated (and yet clinical presentation may be hypothyroid). Usually many doctors would be quick to diagnose hyperthyroidism. This may also be clarified by the well documented increases in reverse T3 but represents an alternative to consider.

Woltman’s sign – The tendon reflex was used effectively to observe low energy states. Poor thyroid regulation meant poor adenosine triphosphate production (ATP or energy compound). Low energy, slowed movement, poor muscle relaxation (Burkholder, Klaas, Kumar, & Boes, 2013)(HOUSTON, 1958). This test has been frowned upon by modern endocrinologists and I’ll add that perhaps even compensatory patterns of adrenaline production and nociceptive, mechanical and pain issues may make the test less than accurate but it still has value in context with the aforementioned tests.

Marker Optimal ranges International

Albumin < 4.0g/dL or 40g/L

Bicarbonate 25-30 mmol/L

Blood pressure Systole < 140 Diastole < 90 mm/Hg (variable)

Iron 8.8 -17. Umol/L

Ferritin Females: 10-122 ug/L Males 33-236 ug/L

TIBC 250-350 ug/L

% Transferrin Saturation 20-35%

RBC Females: 4.0 -4.5 Males 4.2-4.9 x 1012 /L

HGB Females: 135-145g/L Males 140-150 g/L

HCT 0.37-0.44 0.40-0.48

MCV 82-89.9 fL

MCH 28.0 -31.9 pg

RDW <13 %

LDL 5.5+

PRL (non pregnant) Females < 10 ng/L Males < 4 ng/ML

SHBG Female 40-120nmol/L Male 20-60 nmol/L

Tb test 36.5 degrees on waking – 37 degrees after a good meal.

RHR – 70-85 beats per minute.

These tests are recommended for having better conversations about your thyroid function if blood tests come back as normal and yet you feel your blood tests are not reflective of your current health. I don’t for a minute suggest that these are fully diagnostic but hopefully lend to better discussions about thyroid evaluation.

References:

Annamalai, J., & Namasivayam, V. (2015). Endocrine disrupting chemicals in the atmosphere: Their effects on humans and wildlife. Environment International. https://doi.org/10.1016/j.envint.2014.12.006

Barnes, B. (1942). Basal temperature versus basal metabolism. Journal of the American Medical Association, 119(14), 1072–1074. https://doi.org/10.1001/jama.1942.02830310006003

Binita, G., Suprava, P., Mainak, C., Koner, B. C., & Alpana, S. (2009). Correlation of prolactin and thyroid hormone concentration with menstrual patterns in infertile women. Journal of Reproduction & Infertility.

Burkholder, D. B., Klaas, J. P., Kumar, N., & Boes, C. J. (2013). The origin of Woltman’s sign of myxoedema. Journal of Clinical Neuroscience. https://doi.org/10.1016/j.jocn.2012.09.047

Dahiya, K., Verma, M., Dhankhar, R., Ghalaut, V. S., Ghalaut, P. S., Sachdeva, A., … Kumar, R. (2016). Thyroid profile and iron metabolism: Mutual relationship in hypothyroidism. Biomedical Research (India).

Danese, E., Lippi, G., & Montagnana, M. (2015). Red blood cell distribution width and cardiovascular diseases. Journal of Thoracic Disease. https://doi.org/10.3978/j.issn.2072-1439.2015.10.04

Fommei, E., & Iervasi, G. (2002). The role of thyroid hormone in blood pressure homeostasis: Evidence from short-term hypothyroidism in humans. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/jcem.87.5.8464

HOUSTON, C. S. (1958). The diagnostic importance of the myxoedema reflex (Woltman’s sign). Canadian Medical Association Journal.

Oliveira, K. J., Chiamolera, M. I., Giannocco, G., Pazos-Moura, C. C., & Ortiga-Carvalho, T. M. (2018). Thyroid function disruptors: from nature to chemicals. Journal of Molecular Endocrinology. https://doi.org/10.1530/jme-18-0081

Peat, R. (1999). Thyroid Therapies, Confusion and Fraud. Retrieved from www.raypeat.com/articles/articles/thyroid.shtml

Reuwer, A. Q., Twickler, M. T., Hutten, B. a, Molema, F. W., Wareham, N. J., Dallinga-Thie, G. M., … Khaw, K.-T. (2009). Prolactin levels and the risk of future coronary artery disease in apparently healthy men and women. Circulation. Cardiovascular Genetics, 2(4), 389–395. https://doi.org/10.1161/CIRCGENETICS.109.853572