Why did she feel depressed on thyroxine with a normal TSH?

Who is Mary, and why did her low mood keep coming back?

Hashimoto's, fatigue and low mood

Mary was a 52-year-old homemaker and the mother of three boys when she came to the practice where I work as a scientific collaborator. She gave birth to her youngest son at 41, and three years later he was diagnosed with a mild intellectual disability. Mary had been diagnosed with Hashimoto's hypothyroidism six years earlier. At first she felt tired for no clear reason. A few months later, low mood and depressive thoughts appeared.

She had been on levothyroxine ever since, and her endocrinologist was sure that her thyroid was well controlled. His only guide, however, was her TSH and T4 in the blood.

Four psychiatrists, short-lived relief

Mary saw her first psychiatrist at 47 and three more since then. All of them prescribed treatment, and each time it helped for a few months and then stopped working. All of these treatments included at least one SSRI. These medicines let serotonin act longer, and in this way they reduce depressive thoughts. Desperate, Mary also tried controversial treatments, but again found no help.

When I took her detailed history, I could not find one strong clue for a diagnostic plan. The only detail I weighed a little more was that her youngest son has an intellectual disability. As it turned out, it was enough.

How does the DIO2 gene affect active thyroid hormone?

Making the active T3 hormone takes several steps. First, the pituitary gland in the brain produces thyroid-stimulating hormone (TSH). Next, TSH travels to the thyroid gland and tells it to release T4, the inactive pro-hormone with four iodine atoms. Then another enzyme, deiodinase 2 (DIO2), removes one iodine atom and produces the active hormone, T3. Finally, T3 binds its receptors throughout the body and does its work.

Why blood tests can miss it

Several variants of the DIO2 gene make the enzyme less productive. Under certain conditions, when more T3 is needed, the enzyme cannot keep up. One of the best-studied variants is rs225014. In a study of 552 people on thyroxine, 16% carried two copies of this variant (the CC genotype), and they had worse psychological well-being at baseline.¹ Animal studies suggest that up to 80% of the T3 inside the brain is made locally from T4, which helps explain why the variant had no effect on blood thyroid levels.¹

Other variants of the same gene, closely linked with rs225014, were associated with intellectual disability in iodine-deficient areas of China.³ So I asked Mary to do whole genome sequencing and several biochemical and vitamin tests. A urine test for reverse T3, although of low diagnostic value, could also rule out inactivation of the hormone.

What did Mary's tests show?

Mary's DNA showed two copies of the rs225014 variant. This variant has been linked both with poorer psychological well-being on thyroxine and with a better response to combined T4 and T3 treatment, without any change in blood thyroid levels.¹ The authors noted that the results need replication.

In a meta-analysis of observational studies, people with depression had lower vitamin D, and in cohort studies the lowest vitamin D category carried about twice the risk of depression (hazard ratio 2.21).⁴ Whether vitamin D treats or prevents depression still needs trials.

How was Mary treated?

According to the literature, two approaches can support DIO2 function. Kaempferol, a natural flavonoid found in apples, grapes, onions, broccoli and several berries, raised DIO2 activity about 10-fold in human muscle cells.² The second option is combined T4 and T3 treatment.^{1, 5} After a discussion with her endocrinologist, Mary agreed to proceed with both.

Kaempferol from food

• A natural flavonoid in plant foods
• Apples, grapes and onions
• Broccoli and several berries
• About 10-fold higher DIO2 activity in human muscle cells

Combined T4 and T3

• Adds the active hormone directly
• Better well-being in people with the CC genotype
• Blood thyroid levels did not change
• Decided and adjusted by the endocrinologist

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Kaempferol was studied in cells, while combined treatment is a medical decision for the endocrinologist.

Mary reported an impressive benefit from the combined treatment, and she has stayed on it until today. Afterwards, she kept coming only to adjust her treatment and to do preventive tests. This case shows the need for personalised treatment, because small changes to a treatment someone already takes can bring large improvements. Every case is different, so Mary's plan describes her care and is not a plan for anyone else.

Infographic

1. 1

   A long path

   A thyroid tablet passes several steps before it acts. One small change along the path can separate taking it from feeling it.

2. 2

   What blood tests show

   Blood tests show whether a substance is present, not necessarily whether it works.

3. 3

   DIO2 inside tissues

   The DIO2 enzyme turns inactive T4 into active T3 inside tissues, so its activity does not show in blood tests.

4. 4

   A common variant

   One DIO2 variant went with worse well-being on thyroxine and a better response to combined T4 and T3. Results need replication.

5. 5

   Treatment choices

   Combined T4 and T3 treatment is a medical decision for the endocrinologist. Kaempferol was studied in cells.

Sources: Panicker et al. 2009, da-Silva et al. 2007.

gutpathways.com

Save this infographicImage 4:5, with sources, from gutpathways.com

What does Mary's case show about thyroid and mood?

• ▲ Normal T4 and T3 in the blood do not show the levels inside some organs.
• ▲ About one in six people in one large study carried two copies of a DIO2 variant that affects the conversion of T4 to T3.¹
• ▲ Combined T4 and T3 treatment can be discussed with the endocrinologist when symptoms persist, and the gene test can help that discussion.
• ▲ Kaempferol raised DIO2 activity in cells, and foods rich in it are a simple addition to the diet.²
• ▲ In our experience, major stressful events can change how the body handles thyroid hormone.