Graves’ Orbitopathy (GO)
Synonyms: Thyroid Eye disease (TED), Graves’ ophthalmopathy, Endocrine orbitopathy
What is GO?
Graves’ orbitopathy is a chronic inflammatory disease of the orbit which most often occurs together with a thyroid autoimmune disease. Due to dysregulation of the immune system patient immune cells start to produce autoantibodies against the thyroid. These antibodies can stimulate the thyroid and cause uncontrolled production of thyroid hormones. So the patients have far too much thyroid hormone in the blood and clinical symptoms are nervousness, high pulse rate, weight loss, tremor, sweating and others. Half of the patients develop only clinical overt thyroid disease however the other half, mainly the smokers, develop also extrathyroidal manifestations such as most commonly orbitopathy, swellings of the lower legs and joint inflammation.
Why does a patient develop Graves’ disease?
The disease has a strong genetic background (thyroid specific genes and genes of the immune system). Many patients report a family history of thyroid autoimmunity (about 20-30%). All kinds of thyroid autoimmune disease can occur within one family. Many genes are involved, mainly genes which control the function of the immune system. Females are affected significantly more often than men (4-5 times).
Environmental triggers play an important role. Smokers with thyroid autoimmunity are significantly more likely to develop orbital inflammation, more severe orbitopathy and have a worse prognosis for thyroid and orbital diseases. Factors which influence the status of the immune system are involved and may include the GUT microbiota.
How common is GD and GO?
The incidence of Graves’ hyperthyroidism in the general population is about 200 per Million per year (example for Sweden), with a female-to-male ratio of about 4 to 5:1 and peak incidence between 40-60 years of age. The prevalence of moderate-to-severe and very severe orbitopathy in patients with Graves’ hyperthyroidism is fortunately less than 10% in the recent studies. It has been demonstrated that most Graves’ hyperthyroid patients (>80%) without orbitopathy at presentation do not develop orbitopathy after an 18-month follow-up.
What are typical symptoms of GO?
The infiltration of the orbital tissues with autoaggressive cells of the immune system cause local inflammation of the orbital connective tissue of variable degrees. Fortunately most patients develop only mild disease. The most common sign is an inflammation of the lid elevator muscle (M. levator palpebrae). The muscle inflammation causes fibrosis after a while and therefore the muscle shrinks and this results in lid retraction and possible incomplete lid closure. Generally, in the inflammatory phase of the disease, patients experience periocular swelling and redness and complain of pain with eye movements and pressure sensation. Local cells of the connective tissues respond to the inflammation not only with scar formation (fibrosis) but also with fat tissue production. Since the orbit is formed by bones the volume cannot expand and therefore the eyes are pushed outside the orbit which causes exophthalmus. If other eye muscles are involved in the inflammatory process – shrinkage of these muscles can cause squint and double vision. Fortunately only a few patients develop severe sight threatening disease where the orbital tissues expand so much that the optic nerve is compressed and visual acuity drops or when incomplete lid closure causes severe corneal damage.
Graves’ orbitopathy is self-limiting over time but will leave additional tissue and scars with functional defects. Therefore more severe stages should be treated before permanent changes occur.
What can the doctor do to treat GO?
Most important is the collaboration of the thyroid specialist with the ophthalmologist. Well controlled thyroid function is highly beneficial for GO. More than half of the patients experience improvement of GO signs with normalization of thyroid function. GO will be treated according to severity and activity of the disease.
These are patients with mild lid retraction, proptosis no more than 3mm and mild inflammatory signs which allow a rather good quality of life.
These patients can be monitored and can be offered selenium supplementation (200µg/per day).
Moderate to severe stages.
These are patients with more severe manifestations which reduce the quality of life significantly: Proptosis more than 3mm, marked periocular swelling, double vision, and in active status pain and pressure sensation. In active stages patient should be offered anti-inflammatory therapy (mainly infusions with steroids/in the case of relapse or incomplete inactivation: immunosuppression). The response to anti-inflammatory therapy is limited. Inflammation will resolve in 4/5 of the patients within 6-12 weeks. Response of motility impairment and proptosis is unsatisfactory. Squint can even increase during wound healing. The earlier the treatment the better the response.
Persisting defects occur since inflammation induces relatively rapidly scarring and fat production, and this will not resolve due to medical therapy, this can only be corrected by surgery.
However surgery cannot completely reverse the tissue damage but can alleviate most functional deficits and improve appearance considerably. If the patients suffer from acute compression of orbital tissues and/or from marked proptosis – the orbit can be extended by targeted partial removal of the bony orbital walls – with the result of backward movement of the orbital content. Squint caused by shrunken extraocular muscles can be corrected by muscle recessions. This will improve the eye movement and the aim is to eliminate diplopia in primary gaze and downgaze which are the important gaze directions in daily routine. In most of the patients it is not possible to restore binocular single vision in all directions, however squint surgery improves the quality of life of the patients significantly. Another very important part of the surgery is debulking of the lids and lid lengthening to restore complete lid closure and improve appearance.
Sight threatening GO is fortunately rare (about 5%). About half of the patients respond to very high doses of i.v. steroids the others have to undergo bony decompression immediately.
Long term sick leave is not only a socioeconomic burden for the patients. Graves’ orbitopathy takes a lot of patience from the patient. Surgery should only be performed only after at least 6 months of stable thyroid and eye diseases.
Because of the prolonged disease phase – patients need symptomatic treatment before surgery over the whole disease period. The increased ocular surface has to be lubricated with artificial eye drops. Botulinum Toxin can be used to relax shrunken eye muscles – especially the lid elevator muscle can be easily reached via a subconjunctival injection. Lid retraction usually decreases for about 6-12 weeks after a botulinum toxin injection. The individual response to botulinum toxin depends on the grade of fibrosis. Fresnel prisms can be adjusted if diplopia occurs in primary or reading position and help a lot, especially to restore driving ability.
What can the patient do to improve GO or to prevent further deterioration respectively?
The most important is to quit smoking completely. Smokers with thyroid autoimmunity develop significantly more often orbital inflammation, more severe orbitopathy and have a worse prognosis for thyroid and orbital disease. Smoking especially boosts scar formation and therefore smokers suffer six times more often of diplopia in comparison to nonsmokers.
There is evidence that stressful life events promote the development of GO, therefore as far as possible the patients should be advised to seek help in solving conflict areas in their daily life.
What is Microbiota?
It is the aggregate of microrganisms living on our skin, in our mouth and nose, in the genital-urinary mucosa and most notably, in our intestines. Astonishingly the microflora in our intestine weights about 1.5 kilos which is the same weight of our liver and numbers of bacteria total 10,000 times the number of people on the planet.
Up to 1/3 of these billions of microrganisms is inherited from mother during delivery, the remaining is built up during our lives and is influenced by our lifestyle, mainly by diet.
How is the gut microbiota beneficial?
- It helps us to digest food, especially certain types of fibre, providing us with about 5% of our total energy needs as well as being essential in helping us absorb the beneficial antioxidants found in fruits and vegetables
- It acts as barrier to infection, forming a carpet like layer and “blocking” the entry of potentially harmful microorganisms.
- It helps drive the “correct” development of the immune system in the newborn and infant and then primes the immune system for the rest of our lives.
At any one time, the gut mucosa contains about 50% of the cells of the immune system. The interaction between gut epithelium, immune cells and the ‘healthy’ gut microbiota produces proteins which preserve the balance between regulatory immune cells and proinflammatory cells.
In the case of dysbiosis when the microbiota is suboptimal, the balance between regulatory and pro-inflammatory cells is lost. Thus in an individual with a particular genetic predisposition, after dysbiosis, immune cells can react against healthy tissue leading to the onset of autoimmune conditions like Graves’ disease.
What are probiotics and how they can help us?
Probiotics are the friendliest types of bacteria which are found in the normal microbiota. Increase their intake by supplementation can increase fellow bacteria and thus influence not only our gut activity but also our immune reactions.