Good Hope, Heartlands, and Solihull Eye Clinics

Thyroid Associated Orbitopathy (TAO),
thyroid eye disease

David Kinshuck & colleagues

Further information

Thyroid Eye Disease Charitable Trust
PO Box 1928, Bristol, BS37 0AX, England
tel: 0844 800 8113  
ted@tedct.co.uk/   www.tedct.co.uk/

 

 

Thyroid associated orbitopathy (TAO, formerly called thyroid eye disease TED) is described on the sites above. However, there has been tremendous progress in understanding the condition which is very important and not emphasised.

What is the cause of the condition?

First, there are changes in the cells in the orbit, (the area around the eye). The fat cells and muscle cells develop additional 'TSH receptors', and there are antibodies to these. This is the 'autoimmune' stage of the disease.

The second stage: these orbital cells then develop more of the chemical glycoaminoglycans. This chemical attracts water, and so the fat and the muscles around the eye swell up. The swelling pushes the eyes forward and changes the eyelids,

The third stage: the swollen muscles that move the eye cannot work, and the eyes may point in different directions, causing double vision.

Fourth, they eye is pushed forward so much the cornea, the front window of the eye, becomes dry and and may dry out so much it may get infected. Additionally, the fat and muscle swelling may press on the optic nerve reducing eyesight.

These stages represent 'active disease'. With treatment, or even without treatment over about two years on average, the 'autoimmune' phase ends and the antibodies reduce. But the tissues remain swollen, and the 'thyroid eye' appearance of the eyes can remain. This is the 'inactive' or 'hydraulic' or 'stable' stage.
These stages are explained in more detail below. See BJO 15. and BJO 16

"Orbital changes in thyroid orbitopathy (TO) result from de novo adipogenesis, hyaluronan synthesis, interstitial oedema and enlargement of extraocular muscles. Cellular immunity, with predominantly CD4+ T cells expressing Th1 cytokines, and overexpression of macrophage-derived cytokines, perpetuate orbital inflammation. Orbital fibroblasts appear to be the major effector cells. Orbital fibroblasts express both thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R) at higher levels than normal fibroblasts. TSHR expression increases in adipogenesis; TSHR agonism enhances hyaluronan production. IGF-1R stimulation leads to adipogenesis, hyaluronan synthesis and production of the chemokines, interleukin (IL)-16 and Regulated on Activation, Normal T Cell Expression and Secreted, which facilitate lymphocyte trafficking into the orbit. Immune activation uses a specific CD40:CD154 molecular bridge to activate orbital fibroblasts, which secrete pro-inflammatory cytokines including IL-1β, IL-1α, IL-6, IL-8, macrophage chemoattractant protein-1 and transforming growth factor-β, to perpetuate orbital inflammation. Molecular pathways including adenylyl cyclase/cyclic adenosine monophosphate, phophoinositide 3 kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase are involved in TO.
Oxidative stress in TO resulting from imbalances of the oxidation-reduction state provides a framework of understanding for smoking prevention, achieving euthyroidism and the use of antioxidants such as selenium. Progress has been made in the understanding of the pathogenesis of TO, which should advance development of novel therapies targeting cellular immunity, specifically the CD40:CD40 ligand interaction, antibody-producing B cells, cytokines, TSHR and IGF-1R and its signalling pathways. Further studies in signalling networks and molecular triggers leading to burnout of TO will further our understanding of TO. "

Smoking

Smoking increases the TSH receptors in the orbit, and this increases the condition. TAO is up to 7 times worse in smokers  (Bartalena 98), Premmel 1993. That is SEVEN times worse. So do try to stop! The figure relates to approximately 20 cigarettes a day.
Passive smoking, for example if your husband smokes 20 cigarettes a day, means that you will get 25% of his smoke....so if he smokes 20/day and you are in the same room much of the time, your eye disease will be THREE times as severe as if he did not smoke. Eye 16


The active autoimmune autoimmune phase...the TSH receptors

The underlying autoimmune fault is the TSH receptor problems, that is the extra receptors and the extra antibodies to them.

Why does this matter?

The TSH receptor detects TSH that circulates in the blood. TSH is thyroid stimulating hormone, and is made in your pituitary gland. The TSH made in the pituitary gland enters the blood and circulates to all the tissues of the body. The pituitary gland makes more TSH when the amount of thyroid hormone in your blood drops to very low levels. If anyone is short of thyroid hormone, that is if you have had radiation treatment or a high dose of anti-thyroid drugs, or you become short of it naturally, the pituitary gland makes more TSH.

More receptors to TSH

As the immune fault leads to more receptors to TSH on the surface of the orbit cells, these cells become 'extra sensitive' to the TSH.

In addition, the immune fault in TAO leads to antibodies to this TSH receptor. (TSH receptor antibodies, TRAab). The antibodies are produced by the immune system, in 'error'...the immune system thinks the receptors are 'foreign'.

Extra glycoaminoglycans

The extra number of receptors and the extra antibodies stimulate the orbital cells to produce a lot of extra glycoaminoglycans. This causes swelling and fluid accumulation in the cells of the orbit, and so the eye is pushed forward.

So the more TSH there is, the more that will reach the tissues around your eye, and then the more the muscles and fat around your eye will swell up, pushing your eye forward. This is because the TSH makes the cells swell up.

This only occurs in TAO; if the immune system is healthy the high TSH will not affect the eyes, although it will affect other parts of the body.

In TAO we therefore need a low TSH level, or at least one that healthy people have. Therefore patients will need blood checks to see that there is enough thyroid hormone in your bloodstream. Low thyroid hormone leads to higher TSH levels. Reduced blood levels of thyroid hormone stimulates the pituitary gland to make more TSH. This extra TSH makes the orbit cells swell up.

By keeping the right amount of thyroid hormone in the blood, the eyes are much less likely to swell up. If the thyroid hormone levels are low the doctor usually needs to prescribe more thyroxine tablets.

Higher thyroid hormone leads to lower TSH levels.

If the thyroid hormone levels rise, the TSH level drops, and this may reduce the swelling around the eyes a little.
Smoking increases TSH receptors, and makes the condition much worse.

Thyroid antibodies and autoimmunity

As above the TSH receptor antibodies (TRAab) play a critical role in this disease. These are present in the disease, and essentially if the blood level rises the disease becomes more active, and if the levels drop, less active. (2013)

TAO is an 'autoimmune' disease. Autoimmune diseases are diseases when the body produces antibodies or cells that 'attack'  various parts of the body, causing damage and problems. As with other autoimmune diseases, only part of the condition is understood. Smoking increases the autoimmune activity, and steroids and other anti-inflammatory treatment reduces it.

Unlike most other auto-immune diseases, TAO is only usually active for 2 of years, and will become less active naturally. But the TAO may become a severe problem during this active stage in some people, and so during the 2 year period intensive treatment will be need in some people.

However, in most people the condition is not very serious, and steroid treatment etc is not usually needed.

Features of TAO (thyroid eye disease)

TAO causes these problems, which can be scored  by the ophthalmologist.

  1. dry irritable eyes
  2. redness of the conjunctiva...the redness increases as the disease is more active
  3. puffy lids...these become more puffy as the disease is more active
  4. bulgy eyes (proptosis)
  5. raised upper eyelids showing the white above the eye more than usual (lid retraction_
  6. lid lag...when looking down the upper eyelids stay up
  7. these can result in more serious problems
    • stretching and damaging of the optic nerve
    • the fat and muscles in the orbit swell can can compress the optic nerve
    • if the eyes bulges a lot the cornea can become very dry and perforate
  8. problems with eye movements causing double vision etc

Some of these problems get significantly worse when the condition is active, and anti-inflammatory steroid treatment etc may be needed. But some of these problems are not caused by 'active' inflammation, but are caused by fluid accumulation as a result of previous inflammation.

Anti-inflammatory treatment will only work if the disease is active. If the disease is inactive and has resulted in tissue damage and fluid accumulation, surgery can help. The ophthalmologist has to determine which changes are caused by active inflammation, if any, and which are residual effects due to the previously active disease.

For example, the inflammation can cause the eyes to bulge forward, as the tissues in the eye swell. Anti-inflammatory treatment at this stage may reduce the swelling and the eyes will stop bulging. But if the treatment is given late, of if the condition is severe, the inflammation may have disappeared, but the bulging may remain, and surgery may needed to reduce the bulging.

Similarly, eyelid changes in the condition may remain after the 'inflammation' has gone, and the condition is said to be 'stable'. Generally eyelid surgery is not carried out until the condition is stable and all the inflammation had stopped. detail.

Radioactive iodine

Radioactive iodine may cause progression, although corticosteroid therapy starting just before the radioactive iodine may prevent this progression. Radioactive iodine is best avoided with newly diagnosed disease (Graves disease) and active eye disease (Drug & Ther Bulletin 2006).

Metabolic changes in TAO

  1. 33% of Graves disease patients (patients with autoimmune thyroid disease, usually over active) develop TAO.
  2. There are changes in the blood that can be detected by 'metabolomic' test. NMR of the blood
    identifies increased lactate decrease ascorbic acid, both raised in TAO and in patients with Graves disease who then go on to get TAO.
  3. These tests can therefore determine whether the disease is active or not, and whether or not a patients with Graves disease is likely to go on to develop TAO.
    TSH receptor status and ptpn22 gene are also related to disease activity. Essentially the hyperthyroidism is driving the oxidative stress
  4. Antioxidants such as selenium helps, as well as a  healthy diet with plenty of vegetables (and little saturated and transfats) will reduce disease activity.

Thyroid and eye activity

The thyroid disease itself and TAO may not occur at the same time. TAO can occur many years after the thyroid problem, and alternatively TAO may develop years before the thyroid hormone problems themselves are present. More commonly though, TAO occurs a few months or a couple of years after the thyroid and thyroid hormone problem (above). Excellent diagram here.

Sumary of treatment

  1. not smoking
  2. keep TSH slightly low (usually patients need thyroxine or tablets to reduce thryoid function)
  3. plenty of vegetables
  4. it is likely keeping wieght normal and not being overweight will be helpful  see, and exercise probalby will help
  5. selenium supplements :https://www.ncbi.nlm.nih.gov/pubmed/23046013
  6. keep eye lubricated
  7. orthoptist if there is double vision
  8. occasional surgery to lids, or orbit