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THYROID EYE DISEASE (TED)
Thyroid eye disease (TED) is one of the stranger aspects of thyroid disease and particularly interesting from three reasons: first, it is such a bizarre phenomenon making the investigation very interesting; two, it provides some very interesting clues about what causes it and what causes Graves' disease; and third, it can be extremely uncomfortable for the person suffering from it and this makes finding a cure very motivating.
TED is also known as ophthalmopathy, orbitopathy, or exophthalmia. The eyes bulge out and if this becomes severe enough the eyelids no longer close, causing the eye to dry out. Sufferers may have to tape their eyes shut at night to keep their eyes from becoming dry and damaged.
The cause of this bulging of the eye is the growth of fibroblasts at the back of the eye. This tissue grows so much that the eye is pushed outward. Even more interesting is that there is often another growth in the same person--the tissue at the front of the shin, which is also full of fibroblasts, grows and this thickened skin is called pretibial myxedema. This myxedema is sometimes found on the corresponding underside of the lower arm and at other places in the body.
Interestingly, Graves' patients are not the only ones which get TED and pretibial myxedema. People with Hashimoto's thyroiditis also get it and even some people who don't have obvious thyroid dysfunction may get it.
Scientists don't know for sure what causes this fibroblast growth, but studies show that the immune system seems to be involved. Immune system agents called immunoglobins seem to stimulate the growth of the fibroblasts. The same antibodies that seem to cause Graves' and Hashimoto's seem to be the ones involved.
One of the fascinating clues about the cause of Graves', TED, and possibly Hashimoto's is that smokers are more likely than nonsmokers to get all of these conditions. There seems to be something ingested in the tobacco smoke that causes these conditions to develop and worsen.
While there are many substances in tobacco smoke which affect the thyroid, most of these seem to have short-lived effects. I believe that the agent in tobacco which causes thyroid disease must stay in the body a long time.
My theory is that the agent in tobacco smoke which stimulates the onset of Graves' and TED is cadmium. Cadmium is a very toxic heavy metal which is found in the Periodic Table of Elements right below zinc, which in turn is just to the right of copper.
Cadmium is a metal found naturally in soil which is taken up by green leafy plants such as tobacco. Other green leafy plants like lettuce, spinach, beet greens, and Swiss chard also are high in cadmium. Some root vegetables like carrots seem to accumulate cadmium. The fact that cadmium is taken up by these plants and humans and other animals eat and enjoy these plants suggests that cadmium might be an essential nutrient.
There is a protein in the body called metallothionein, which is formed from the amino acid cysteine, that transports cadmium, zinc, copper and possibly other metals in the body. It's possible that excessive cadmium competes for transport sites with copper and zinc and may even be preferentially transported by metallothionein and this is the reason why cadmium in excessive amounts is so toxic to the body.
Cadmium is a very useful metal because it provides corrosion resistance and has electrical properties. It is used extensively in industry and cadmium waste goes into the sewage system. Sewage sludge is an inexpensive fertilizers used in agriculture. Because of growing awareness of the high cadmium content and the dangers of cadmium are becoming more well known, most progressive and organic farmers do not use sewage sludge. However sewage sludge is still used in some agriculture. Tobacco is one of the crops which are fertilized extensively with sewage sludge, and this is one reason why tobacco is so high in cadmium. However, even tobacco not fertilized this way has high cadmium because the plant naturally accumulates cadmium from the soil. When tobacco is smoked, relatively large amounts of cadmium are ingested into the body.
Batteries are another source of cadmium. Ni-Cad or nickel-cadmium batteries are used extensively and we all handle these. It is highly likely that cadmium particles cling to the outside of these batteries and we may ingest this cadmium if we don't thoroughly wash our hands after handling these batteries.
There are some very big problems with cadmium entering the body. First of all, cadmium is known to be toxic to the thyroid gland cells. Thyroid cells can be taken from an animal and put into a dish and kept alive. Then various substances including heavy metals can be added to the cells to study the effects. From these studies cadmium has been determined to be a metal which is particularly damaging to thyroid cells. It's not surprising that smoking might cause thyroid malfunction.
Another interesting thing about cadmium is that female animals tend to accumulate cadmium while male animals tend to not accumulate it as much. This is an extremely strange phenomenon but it lends support to the theory that cadmium is a culprit in autoimmune thyroid disease and TED.
Consider these experiments: Scientists took male and female rats and castrated them, thereby eliminating the bulk of their naturally produced sex hormones, testosterone and estrogen. Then they gave half the animals (both male and female) cadmium. The groups were further divided so that half of each group was injected with testosterone and half with estradiol (the most potent of the estrogens). The animals that were given estradiol, whether male or female, were found to accumulate cadmium, and the animals given testosterone were found to excrete the cadmium. By this experiment it was shown that estrogen (estradiol) causes the accumulation of cadmium, while testosterone causes the excretion of cadmium.
What does this mean? It means that women are much more likely to accumulate cadmium and to suffer from the toxic effects of cadmium. (I will discuss this situation in more detail in the cadmium story.) Since women make up close to 90% of thyroid disease cases, this offers very suggestive evidence that cadmium might be an important factor. Women's bodies are not well suited for being exposed to toxic metals.
Another interesting aspect of TED is that studies show that TED increases following radioiodine therapy (RAI). When you think about it, this is a very strange, but intriguing phenomenon also.
My feeling is that this might also be connected to cadmium. When radioactive iodine is administered in RAI, we know that this radioiodine must break down into alpha particles and other elements. Iodine is element number 53, so when it breaks down it presumably breaks down into elements with smaller atomic numbers.
Cadmium is element number 48, only five elements below iodine. It's possible that as radioiodine breaks down into cadmium which is the stable breakdown product. I hope to find out if this is possible, but this would fit in with the observations and theory that cadmium toxicity is a prime cause of TED and Graves'.
If the theory that cadmium toxicity is a major causative factor in TED and Graves', then there is another bizarre conclusion: that consumption green leafy vegetables might be very damaging to sufferers of Graves' and TED. I have to laugh every time I think about this because it is a very strange conclusion. It's extremely difficult for me or most people to think of salads filled with green leafy vegetables as possibly being culprits in Graves'.
Remember that this is just a theory, but interestingly this agrees with my experience when I had hyperthyroidism. It seemed that whenever I ate a green salad my hyper symptoms would increase and that night would be a more difficult night than usual.
Also, recently I met a woman who was the first person I've known with TED. I was amazed at how her eyes protruded and she told me that she had just concluded a series of ten radiation sessions in which the radiation was directed to the fibroblasts at the back of the eyes. I felt very sorry for her--it's not a pretty sight.
I explained many of my theories to her including the one about how eating green leafy vegetables might be very damaging because of the cadmium content. I was very amazed when she told me that she practically lived on salads loaded with green leafy vegetables. This is just observation, but it didn't contradict the theory. Pretty strange theory, if true.
March 5, 2002
Some group members have said that flax seed oil or eggs from chickens fed flax seed oil have benefited their thyroid eye disease. It's definitely worth a try.
The following study may be extremely significant for the understanding of Graves' disease and Graves' ophthalmopathy (TED). While I hesitate to jump to conclusions, this study seems to indicate that manganese superoxide (MnSOD), which is an antioxidant, may stimulate retroocular fibroblast growth which is the root of TED. The retroocular fibroblasts seem to grow in response to stimulation by the TSH receptor antisera (anti-p1). MnSOD has a similar structure to the TSH receptor peptide and apparently in Graves' there is an autoimmune response to MnSOD. Therefore it is possible that an excess amount of manganese in the diet causes excessive production of MnSOD which in turn causes and autoimmune response to MnSOD and this stimulates the retroocular fibroblasts. While this would be very interesting, I don't know if my interpretation of this is correct. However, this does fit in with the fact that manganese is a copper antagonist and high levels of manganese would suppress copper levels. Copper supplementation could, in turn, help reduce manganese levels and help suppress this autoimmune response.
Immunodetection of manganese superoxide dismutase in cultured human retroocular fibroblasts using sera directed against the thyrotropin receptor.
Burch HB, Barnes S, Nagy EV, Sellitti D, Burman KD, Bahn RS, Lahiri S
Endocrine-Metabolic Service, Kyle Metabolic Unit, Walter Reed Army Medical Center, Washington, DC 20307-5001, USA.
The identification of antigenic targets in the retroocular autoimmune response of Graves' ophthalmopathy is likely to increase our understanding of mechanisms underlying this disorder. While a number of putative autoantigens have been identified on the basis of molecular weight or cell of origin, a determination of the significance of these antigens is contingent upon an identification of the amino acid sequence. Our group has previously identified immunoreactive retroocular fibroblast (ROF) proteins recognized by thyrotropin receptor (hTSH-R) antisera (anti-p1), at molecular weights of 95, 71, 41, and 14-25 kDa. In the present study, proteins detected by anti-p1 and visualized by Ponceau staining were isolated and processed for microsequencing. Ponceau staining revealed dense bands at molecular weights of 14 and 23 kDa, and a weak band at 41 kDa. N-terminal sequencing was performed on the prominent band at approximately 23 kDa, showing it to be manganese superoxide dismutase (MnSOD), a mitochondrial enzyme responsible for protection against oxygen free radical-associated cellular damage. Sequence comparison of MnSOD to the hTSH-R peptide, p1, revealed a linear segment of amino acid homology. Preincubation of anti-p1 with p1 blocked immunodetection of the 23 kDa band corresponding to MnSOD, and immunoprecipitation of ROF protein using anti-pi yielded protein recognized by anti-MnSOD. Autoimmunity against human recombinant MnSOD was further assessed by ELISA. Patients with Graves' disease (n = 53) had significantly higher ELISA indices than normal control subjects (n = 29), while patients with Hashimoto's thyroiditis had intermediate values. These results document MnSOD autoantibodies in patients with Graves' disease and suggest that this may result from an immune cross-reactivity between MnSOD and the TSH-receptor.
The following study suggests that selenium deficiency is involved in fibrosis. This proliferation of fibroblasts is also seen in Thyroid Eye Disease, therefore this condition may be a result of selenium deficiency.
Selenium deficiency and thyroid fibrosis. A key role for macrophages and transforming growth factor beta (TGF-beta).
Contempre B; Le Moine O; Dumont JE; Denef JF; Many MC
Institute of Interdisciplinary Research (IRIBHN), Free University of Brussels, Medicine Faculty, Belgium. firstname.lastname@example.org
Mol Cell Endocrinol, 124(1-2):7-15 1996 Nov 29
AbstractFree radical damage and fibrosis caused by selenium deficiency are thought to be involved in the pathogenesis of myxoedematous cretinism. So far, no pathway explains the link between selenium deficiency and tissue fibrosis. Pharmacological doses of iodine induce necrosis in iodine-deficient thyroids. Necrosis is much increased if the glands are also selenium-deficient, which then evolve to fibrosis. This rat model was reproduced to explore the role of selenium deficiency in defective tissue repair. At first, proliferation indexes of epithelial cells and fibroblasts were comparable between selenium-deficient and control groups. Then, in selenium-deficient thyroids the inflammatory reaction was more marked being mainly composed of macrophages. The proliferation index of the epithelial cells decreased, while that of the fibroblasts increased. These thyroids evolved to fibrosis. TGF-beta immunostaining was prominent in the macrophages of selenium-deficient rats. Anti TGF-beta antibodies restored the proliferation indexes, and blocked the evolution to fibrosis. In selenium deficiency, an active fibrotic process occurs in the thyroid, in which the inflammatory reaction and an excess of TGF-beta play a key role.
The following is a study which suggests that a bone marrow transplantation cured Graves', TED, and anemia. This could also be interpreted that the Graves' and TED were caused by the anemia and correction of the anemia by the bone marrow transplantation corrected these conditions. The bone marrow is where the red blood cells are manufactured. Be aware that this is just one case and not scientific evidence.
The following study shows that radiation therapy for ophthalmopathy (TED) does not produce any beneficial effects that can be measured (by the methods used in this test). There does not seem to be any benefit from radiotherapy, leaving only the negative effects of radiation. I see absolutely no reason to undergo radiation therapy for TED.
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND CONTROLLED STUDY OF ORBITAL RADIOTHERAPY FOR GRAVES' OPHTHALMOPATHY.
C. Gorman, J. Garrity, V. Fatourechi, R.S. Bahn, I. Petersen, S. Stafford, J. Earle, G. Forbes, R. Kline,E. Bergstralh, K. Offord, D. Rademacher, N. Stanley and G. Bartley Division of Endocrinology and Departments of Ophthalmology, Radiation Oncology, Diagnostic Radiology and the Section of Biostatistics, Mayo Clinic, Rochester, Minnesota USA and University of California Davis at Sacramento, Division of Radiation Oncology, Sacramento, California USA
Background: Although widely used for treatment of Graves' ophthalmopathy (GO), the efficacy of orbital radiotherapy (OT) has not been established in a prospective randomized double-blind controlled trial.
Specific aims: To determine: 1) If 20 Gy of external beam OT directed to one orbit of patients with GO resulted in improvement in comparison with the untreated orbit when evaluated three and six months after therapy; 2) If 20 Gy of OT to the second orbit six months later produced effects similar to those observed when the first orbit was treated; 3) To relate the magnitude of the treatment effect to the time since onset of eye symptoms.
Patients and Methods: Forty-two euthyroid patients with mild to moderate GO and elevated TSI levels received 20 Gy of megavoltage radiation to a randomly selected orbit. Six months later the second orbit was treated. Every three months, measurements were made of thyroid function and antibody status, proptosis, volume of extraocular muscle (EOM) and fat, range of EOM motion, eyelid fissures and extent of diplopia. The study had 80% power to detect 0.5 mm change in proptosis and 0.75 mL in volume measures.
Results: Six month - baseline measurements were recorded for the untreated (UT) and the treated (T) orbit. They revealed (mean±SD): Fat volume(cc) UT -0.3(1.3), T 0.3(1.3), P 0.87. Muscle volume(cc) UT -0.4(1.3), T -0.6(1.4), P 0.14. Proptosis(mm) UT 0.0(1.0), T -0.1(1.3), P 0.46. Range of motion area (cm2) UT 8.7 (33), T 8.8(35), P 0.98. Lid fissures(mm) UT 0.0(2.0), T -0.1(1.7), P 0.42.
Results at three months were similar to those at six months. Diplopia field area at baseline, six and 12 months was 42, 41, and 39 cm2. P=0.09 for six months - baseline and 0.02 for 12 months - baseline. Subset analyses of early vs. late treated orbits, or smokers vs. non-smokers, and of patients treated <1.3 vs. >1.3 years since onset disclosed no significant differences for any group.
With one exception, patients were euthyroid on commencing and throughout the study.
Conclusion: If radiotherapy is beneficial for Graves' ophthalmopathy, its ameliorative effects did not reach the detection level of the techniques used in this study. No clinically significant benefit was observed.
Radiotherapy Does Not Help Graves' Disease Eye Problems
For years, radiation therapy to the eye has been used to treat eye problems associated with the thyroid condition Graves' disease. Now a new study questions whether this treatment is actually useful.
Graves' disease triggers an overproduction of hormones from the body's thyroid gland, a key regulator of metabolism and other vital functions. A small percentage of people with the disorder have a complication called Graves' ophthalmopathy, which is characterized by bulging eyes, double vision and other eye problems.
To investigate the effectiveness of radiotherapy for these eye complications, investigators studied 42 patients with Graves' ophthalmopathy. The patients exhibited a variety of symptoms including higher-than-normal volumes of eye muscle and fat, bulging of the eyes, less eye range of motion and double vision.
The patients received radiotherapy in one eye and a "sham" treatment in the other eye.
At follow-up, 3 and 6 months after treatment, no significant differences were observed between the treated and untreated eyes.
And this was true regardless of whether a patient was a smoker. Smokers, the researchers note, have been found to be more vulnerable to Graves' ophthalmopathy, and this could theoretically affect their response to treatment.
Graves' disease is a naturally remitting condition, and over a period of time many of the symptoms, including [those related to] the eyes, may improve. This tendency to natural remission, together with the imprecision of measurements used in most previous studies, has allowed the perception to persist that the treatment is effective.
Overall, in 44% of the patients, the eye treated with radiotherapy did not appear any different from the non-treated eye. In about 27% of patients the treated eye appeared better than the untreated eye, but in 30% it appeared worse.
Ophthalmology September 2001;108:1523-
Mary Shomon told me about a website called www.TEDCURE.com.
When potassium is deficient the cell membrane allows more water to enter the cell than escape so cells swell up with water. This is manifested in people as edema and many hypers report gaining weight on very little calorie intake and generally having edema. Myxedema which is another form of edema and which is seen in Graves' as pretibial myxedema or orbital fibroblast proliferation may have the same origin: from potassium deficiency. I consider it quite likely that potassium deficiency is a major contributing cause to TED and worthy of further investigation. However, I doubt if potassium deficiency is the only cause. Most likely it is one of several deficiencies whose combination leads to the condition.
Following is a list of potassium deficiency symptoms from Dr. Gupta's website:
This problem of K-loss results in early maturity, early decay and early death.
The following study shows that smoking and RAI greatly increase the risk for developing Thyroid Eye Disease. Also note
Risk factors for thyroid optic neuropathy include smoking, radioactive iodine treatment
Patients should be followed closely. Visual-field and color-vision testing help in early detection.by Bob Kronemyer
WAIKOLOA, Hawaii — Smoking and radioactive iodine treatment alone are two risk factors for developing thyroid optic neuropathy among patients with Graves’ hyperthyroidism.
“We now know that smoking is a significant risk factor,” said Robert L. Lesser, MD, a neuro-ophthalmologist in private group practice in Waterbury, Conn. “This is another reason to warn these patients that they should not be smoking. In fact, patients who have thyroid disease in general are seven times more likely to develop a more severe form of ophthalmopathy if they smoke.”
Blindness following orbital irradiation for Graves' ophthalmopathy.