Many conditions are associated with impaired thyroid transport, including insulin resistance, diabetes, depression, bipolar disorder, high cholesterol and high triglycerides levels, chronic fatigue syndrome, fibromyalgia, and diseases of the brain and nervous system such as migraines, Alzheimer’s, Parkinson’s and multiple sclerosis. Low intracellular thyroid hormone can result from stress, anxiety and chronic dieting and aging (Holtorf, 2014b).

Toxins and other substances produced by the body in response to physiologic stress and calorie reduction interfere with cellular uptake of thyroid hormones. Since thyroid hormone uptake in the pituitary is relatively unaffected by outside factors, drugs such as benzodiazepine medications, including diazepam (Valium®), lorazapam (Atavan®) and alprazolam (Xanax®) can prevent T3 uptake into the cells of the body, but have no effect on movement of T3 into the pituitary (Kragie & Doyle, 1992).


Eighty metabolic genes responding to thyroid all need iron, which is lower when hepcidin from your liver is elevated in response to inflammation.  High inflammation also interrupts the conversion of inactive T4 to active T3 inside tissue cells of the body. The result is a cellular hypothyroidism, even in the presence of normal T4 and T3, and is known as Peripheral Tissue Hypothyroidism.

On a lab test you will see: TSH is normal, T4 is normal, T3 is low and RT3 is high, indicating that inflammation is a problem, possibly due to autoimmune disease. In these scenarios, the elevations in inflammatory cytokines are depressing thyroid receptor site responsiveness while the hormones create a normal appearance of thyroid markers (TSH, T4 and T3).

Many autoimmune patients will not notice any difference even when taking T4 thyroid hormone because of decreased receptor site sensitivity and decreased conversion of T4 to T3 (Kharrazian, 2009).  As you correct the underlying inflammation, these patients do better with glandular thyroid or bioidentical hormones which contain time released T3.


Figure 6.29 Abnomal thyroid physiology

Thyroid hormones enzymes, known as deiodinases, control activation and deactivation of thyroid hormones cells.

Three different deiodinase enzymes present in different tissues in the body (Holtorf, 2014a):

  • Type 1: D1 deionodase converts inactive T4 to active T3 throughout the body. (Bianco, Salvatore, Gereben, Berry, & Larsen, 2002).
  • Type II: D2 deiondinase activity determines pituitary T3 levels (Kaplan, 1984).

D2 is 1000 times more efficient at converting T4 to T3 than the D1 enzyme present in the rest of the body (Zavacki et al., 2005) and is much less sensitive to suppression by toxins and medications. In contrast to the rest of the body that is regulated by both D1 and D3, the pituitary contains little D1 and no D3 (Silva, Dick, & Larsen, 1978).

Additionally, D2 in the brain has an opposite response from that of D1 in the tissues to physiologic and emotional stress, depression, both dieting and weight gain, PMS, diabetes, leptin resistance, chronic fatigue syndrome, fibromyalgia, inflammation, autoimmune disease, and systemic illness. Pituitary D2 is stimulated and up-regulated in response to such conditions, increasing T4 to T3 conversion while the rest of body suffers from dropping levels of active T3.This causes the TSH to remain normal despite the fact that there is significant cellular hypothyroidism present in the rest of the body.

On the other hand, with reduced T4 levels, the activity and efficiency of D1 in the target cells decreases (Berry, Banu, & Larsen, 1991), resulting in a reduction in cellular T3 levels while the TSH remains unchanged due to the ability of the pituitary D2 to compensate for the diminished T4.

  • Type III: D3 deiodinase reduces cellular thyroid activity by converting T4 to the anti-thyroid reverse T3 (reverse T3)19 (Peeters et al., 2005).

The pituitary is the only tissue that does not contain D3, which converts T4 to reverse T3 and D3 competes with D1 that converts T4 to T3 (Islam, Yesmine, Khan, & Alam, 2008).

Reverse T3 is a competitive inhibitor of T3, blocking the active thyroid hormone T3 from binding to its receptor and blocking T3 effect. This reduces metabolism, suppresses D1, reducing conversion of T4 to T3, (Tien, Matsui, Moore, & Negishi, 2007) and blocks T4 and T3 uptake into the cell (Mitchell, Manley, Rowan, & Mortimer, 1999).The result is a reduction of intracellular T3 levels and thyroid activity as the result of the abundant presence of  D3 enzyme in tissues levels and complete lack of pituitary D3 enzyme (Kaplan, 1984).

Thyroid hormonal interactions


The inhibitory effects on the peripheral tissues causing hypothyroidism are not reflected by TSH testing. Because increased serum and tissue level of reverse T3 blocks the thyroid receptors, even small increases in reverse T3 can result in a significant decrease in thyroid action and result in severe hypothyroidism not detected by standard blood tests (Santini, Chopra, Hurd, Solomon, & Teco, 1992).

T4 supplementation will contribute to more reverse T3; T4 only treatments should not be considered optimal thyroid replacement in the presence of high or high-normal reverse T3 levels (Samuels, Schuff, Carlson, Carello, & Janowsky, 2007); the use of T3 is beneficial and should be used in these conditions (Pingitore et al., 2008).

New information on differences in at the cellular level between the pituitary cells in the brain and the cells that make up the tissues in the rest of the body has lead to new standards for addressing thyroid disease.

The reliability of what has historically been considered standard thyroid testing for TSH and T3 is obsolete when cellular hypothyroidism is a result of low intracellular T3 and elevated blood levels of T4. New standards for evaluating and treating thyroid disorders are discussed in Volume 8, Master Hormones.


Traditional thyroid screening involves testing blood levels of circulating thyroid hormones. Thyroid hormone transport across cellular membranes is called autocrine or intracellular signaling. This form of hormone communication plays an important role in intracellular thyroid hormone levels and is proving to have considerable clinical significance.

Thyroid hormones can be prevented from entering the mitochondria by low cortisol as a result of adrenal fatigue.

Your body down regulates thyroid in the presence of heart disease to protect the heart. It is not wise to stimulate the thyroid gland before diagnosing potential problems with the heart.

Increases in rT3 levels are mainly a result of reduced transport of T4 into the cell and not due to increased T4 to rT3 conversion by D3 deiodinase enzyme.

High reverse T3 is a condition reflecting either an inhibition of reverse T3 uptake into the cell and/or there is increased T4 to reverse T3 formation (Hennemann, Vos, de Jong, Krenning, & Docter, 1993).

Due to rT3 and T4 transporters being equally energy dependent, a high serum rT3 has been shown to be a marker for reduced uptake of T4 into the cell (Hennemann et al., 1993). Reverse T3 is a reliable marker for identifying reduced cellular T4 and T3 levels that would not normally be detected by TSH or serum T4 and T3 tests (Hinz et al., 2015).

When this occurs, T4-only replacement is not advised. While a high rT3 can occasionally be associated with hyperthyroidism, as the body tries to reduce cellular thyroid levels. More often, identifying symptoms and using the free T3/rT3 ratio, which correlates with intracellular thyroid levels leads to a better analysis of the problem (van den Beld et al., 2005). A physician should test for indications of mitochondrial disease an analysis of imbalances of thyroid hormones,  as low ATP production would affect active transport of these hormones

Symptoms to look for when diagnosing hypothyroidism include fatigue, weight gain, depression, cold extremities, muscle aches, headaches, decreased libido, weakness, cold intolerance, water retention and PMS. It is best to use a combination of both clinical and laboratory assessments to determine the likely overall thyroid status.

A free T3/reverse T3 ratio of less than 0.2 being a marker for tissue hypothyroidism (when the free T3 is expressed in pg/mL (2.3–4.2 pg/mL) and the reverse T3 is expressed in ng/dL (8–25 ng/dL), (van den Beld, Visser, Feelders, Grobbee, & Lamberts, 2005).


A therapeutic trial of straight time released Liothyronine (SRT3) or Nature-Throid (T4/T3 combination therapy) can then be instigated in the presence of an elevated TSH.

In 2009, the 11th European Congress of Endocrinology released research showing that T3 supplementation can be significantly beneficial (Batterham, Le Roux, et al., 2003) in the presence of high or high-normal reverse T3 levels (Gomberg-Maitland & Frishman, 1998) compared to standard T4. Sustained release T3 is available from compounding pharmacies such as Liothyronine SR. When combined with supplemental ATP to drive transporter uptake by the cells, sustained release T3 can be extremely beneficial. Following up with immune system support and detoxification can further restore proper thyroid hormone balance.