Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy

Posted on January 21, 2011 by gravity

Summary

This study examined whether symptoms of Grave’s opthalmopathy (GO) were associated with patients’ levels of thyroid antibodies and/or levels of thyroid hormones. The hypothesis is that patients with high antibody levels and/or high thyroid hormone levels would have more severe symptoms of GO.

The authors did this study by looking back through the medical records of patients at their hospital. In total, they found records from 182 Grave’s patients who developed GO. Of these patients, when the GO developed, 143 were hyperthyroid (high levels of thyroid hormones), 28 were euthyroid (normal levels of thyroid hormones), and 11 were hypothyroid (low levels).

The sex, age, and smoking status of the patients were not correlated with their development of GO. This is interesting because other articles have shown that smoking greatly increases the risk of GO.

Thyroid hormones: Thyroid hormone levels were important in the development and the severity of GO. Patients with low or normal thyroid hormone levels (hypothyroid and euthyroid patients) had less severe GO than hyperthyroid patients did. The amount of steroid given to treat the GO was the same for everyone, but the need for irradiation therapy was less in the hypothyroid and euthyroid groups. This shows the importance of getting the thyroid hormone levels down to decrease the severity of GO.

Antibodies: The authors looked at two antibodies associated with Grave’s Disease. Normally people produce antibodies to foreign “germs” as part of the body’s immune defenses. Sometimes however, people produce antibodies against their own body, leading to an autoimmune (self-immune) problem. In many people with Grave’s Disease, their body produces antibodies that fight the thyroid gland. Two of these antibodies include TRAb (thyroid antibody) and TPOAb (thyroid peroxidase antibody). The authors looked at the level of these two antibodies in the patients before, during, and after the patients developed GO.

TRAb levels were higher in hyperthyroid patients than in euthyroid or hypothyroid patients. TPOAb levels didn’t differ between the groups. After 6 months of treatment for GO, only 69% of the euthyroid and hypothyroid patients still had elevated TRAb levels, but 94% of the hyperthyroid patients still had elevated levels. Also, 25% of the euthyroid and hypothyroid patients had no TRAb or TPOAb, while only 5% of the hyperthyroid patients didn’t have these antibodies. It’s hard to know in studies like this what is the cause and what is the effect. Did patients whose Grave’s Disease was naturally going away have less GO because of that? Or did treatment reduce the GO? It is clearly possible to have Grave’s Disease and/or GO without antibodies against the thyroid. Perhaps there are other antibodies being produced that we don’t have tests for yet. The bottom line is that people with lower thyroid hormone often also had lower antibody levels. However, whether that is a cause or a result of their treatment is unclear.

Some people developed GO before they got diagnosed with Grave’s. In fact, 25% of people with GO developed thyroid problems within 4 years. The authors suggest that thyroid levels be checked regularly in people with GO, even if their thyroid levels are currently normal.

Bottom line: patients with well-managed thyroid levels had less severe GO and lower thyroid antibody levels.

Reference

A K Eckstein et al., “Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy,” British Journal of Ophthalmology 93: (2009): 1052 -1056.

Abstract:
Retrospective, observational study to compare clinical symptoms and TSH-receptor antibodies (TRAb) in Graves ophthalmopathy (GO) in euthyroid and primarily hypothyroid patients to those in hyperthyroid patients.Methods: Clinical symptoms (NOSPECS (severity) and CAS (activity) score), prevalence and levels of thyroid specific antibodies and the course of the disease were evaluated in 143 primarily hyperthyroid, 28 primarily euthyroid and 11 primarily hypothyroid patients with GO.Results: Patients with euthyroid/hypothyroid GO developed significantly less severe GO symptoms (NOSPECS score 4.4 vs 5.7; p = 0.03), less active GO (CAS score 3.9 vs 5.2; p = 0.002) and more asymmetrical disease (proptosis side difference: 1.9 mm vs 1.0 mm (p = 0.01); side difference of ⩾3 mm: 23% vs 4.8%) than hyperthyroid patients. TRAb levels 6 months after GO onset were significantly lower (2.2 IU/l, p = 0.02) in euthyroid/hypothyroid than in hyperthyroid patients (8.6 IU/l), as was the prevalence of both TRAb and thyroid peroxidase antibodies (75% vs 94.6%, p = 0.0008).Conclusions: The knowledge about the phenotype of GO in primarily euthyroid and hypothyroid patients is helpful for differential diagnosis and patient consultation. TRAb titres are very low in these patients, and the availability of a sensitive assay technique is therefore an important diagnostic tool in euthyroid and hypothyroid patients.




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Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves’ disease

Posted on January 4, 2011 by gravity

Summary

This paper looked at the genetics of patients with either Hashimoto’s Thyroiditis or Graves’ Disease. Both of these diseases are currently thought to autoimmune disorders, like type II diabetes or allergies. Specifically, in thyroid disease, the body produces an “wrong” antibody that, when circulating in the blood, can bind to the surface of thyroid gland cells. Normally, Thyroid Stimulating Hormone (TSH) would beind to these receptor cells and cause the thyroid to produce thyroid hormone. The specificity should be like a lock and key. However, in thyroid disease, it is thought that the body produces an antibody that is similar enough to the TSH “key” to work in the receptor “lock”, thereby confusing the thyroid into producing more thyroid hormone, even when there is no TSH around.

The authors of this paper looked at the gene for the TSH receptor (TSHR) in thyroid patients to see if there were any known genetic places that would cause this. They found 28 places that were “associated” with Grave’s disease – meaning that some GD patients had that particular variation in that location. However, there was a lot of variability in the data. Some GD patients had none of the variants, while some normal people had several. The authors talk about how this is typical of diseases with a genetic component. When you actually dig down to see what cellular changes happen as a result of the genetic difference, the results are muddied.

The upshot? Don’t look for a genetic test for GD anytime soon, and a multitude of factors, not just genetics, determines who develops symptomatic GD.

Reference:

Brand, O.J., Barrett, J.C., Simmonds, M.J., Newby, P.R., McCabe, C.J., Bruce, C.K., Kysela, B., Carr-Smith, J.D., Brix, T., Hunt, P.J., Wiersinga, W.M., Hegedus, L., Connell, J., Wass, J.A., Franklyn, J.A., Weetman, A.P., Heward, J.M. & Gough, S.C. (2009) Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves’ disease. Hum. Mol. Genet., 18, 1704-1713.

Abstract: Graves’ disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclu- sive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (x2 = 32.45, P = 8.90 3 1028, OR = 1.53, 95% CI = 1.32–1.78) and rs12101255 (x2 = 30.91, P = 1.95 3 1027, OR = 1.55, 95% CI=1.33–1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 3 1024). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.

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Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review

Posted on January 3, 2011 by gravity

Summary

This paper was a “meta-study”, meaning that they did no new research themselves, but instead did a statistical analysis of many existing papers to bring all the various studies together. The paper is quite readable and I recommend reading the original (link at bottom). Specifically, the authors examined multiple earlier studies to see whether radioiodine treatment caused or worsened Grave’s opthalmopathy (GO, Grave’s eye disease). The short summary is YES – RAI leads to a 20% chance of developing or worsening GO. I apologize in advance – some of the sentences below are verbatim quotes but I lost track of what bits are mine and what are quotes.

RAI does cause an increased risk of eye problems, but taking prednisolone prevents this.
The authors found that, when compared with antithryoid drugs (ATD) or surgery, radioiodine treatment (RAI) was associated with increased risk of severe ophthalmopathy (opthalmopathy that requires treatment). However, in patients who received RAI, treatment with prednisolone was very effective in preventing worsening of eye disease in patients with pre-existing ophthalmopathy. Among 88 patients who already had GO, it got worse in 26 of them. However, none of the 96 patients who received prednisolone developed worsening of GO. In patients with no pre-existing eye disease, GO developed in 6 out of 88 patients after REI, but in ZERO out of 75 patients who took prednisolone. Unlike the success of prednisolone, the use of ATD after RAI does not prevent GO. No participant receiving prednisolone in these trials developed severe ophthalmopathy. In fact, in some patients with pre-existing ophthalmopathy, the use of prednisolone was associated with some improvement in GO, despite RAI.

Sicker patients have more eye disease.
Patients who had a starting serum T3 level of more than 5 nmol/l (ie, more severe Grave’s Disease to start with) had a greater risk of developing or worsening GO no matter what therapy they used. Also, smoking greatly increases the risk of GO.

Letting patients go hypothyroid after RAI can lead to eye disease
Untreated hypothyroidism following RAI is thought to be an important risk factor for developing GO. One study found that deterioration of GO in patients with mild GO might be prevented by early administration of T4 after RAI treatment.

Clinical take-home messages (Direct quote from paper)

  • Radioiodine therapy for Graves’ disease is associated with increased risk of occurrence or progression of ophthalmopathy compared with antithyroid drugs.
  • The risk of developing new ophthalmopathy or worsening of pre-existing ophthalmopathy is around 20% after radioiodine and around 5% after antithyroid drugs. The risk of developing severe ophthalmopathy after radioiodine therapy is around 7%.
  • Smoking, high levels of pretreatment serum T3 (twice the upper limit of normal) and post radioiodine hypothyroidism are associated with increased risk of ophthalmopathy.
  • A high TSH-receptor antibody titre is an independent risk factor for the progression of ophthalmopathy.
  • Post radioiodine hypothyroidism should be treated promptly. In patients with mild pre-existing ophthalmopathy, prednisolone prophylaxis is effective in preventing deterioration.
  • Routine use of prophylactic steroids with radioiodine therapy is not indicated at present but should be considered in patients at higher risk of eye complications (e.g. smokers).

    • We also recommend a minimum specialist follow-up of 12 months following RAI since, in most cases, GO develops or worsens at around 6 months.

    Reference

    Acharya, S.H., Avenell, A., Philip, S., Burr, J., Bevan, J.S. & Abraham, P. (2008) Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review*. Clinical Endocrinology, 69, 943-950.

    Background An association between radioiodine therapy (RAI) for Graves’ disease (GD) and the development or worsening of Graves’ ophthalmopathy (GO) is widely quoted but there has been no systematic review of the evidence.Aims We undertook a systematic review of randomized controlled trials (RCTs) to assess whether RAI for GD is associated with increased risk of ophthalmopathy compared with antithyroid drugs (ATDs) or surgery. We also assessed the efficacy of glucocorticoid prophylaxis in the prevention of occurrence or progression of ophthalmopathy, when used with RAI.Methods We identified RCTs regardless of language or publication status by searching six databases and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Random effects meta-analyses were used to combine the study data. Ten RCTs involving 1136 patients permitted 13 comparisons. Two RCTs compared RAI with ATD. Two RCTs compared RAI with thyroidectomy. Four RCTs compared the use of adjunctive ATD with RAI vs. RAI. Five RCTs examined the use of glucocorticoid prophylaxis with RAI.Results RAI was associated with an increased risk of ophthalmopathy compared with ATD [relative risk (RR) 4·23; 95% confidence interval (CI): 2·0420138·77] but compared with thyroidectomy, there was no statistically significant increased risk (RR 1·59, 95% CI 0·8920132·81). The risk of severe GO was also increased with RAI compared with ATD (RR 4·35; 95% CI 1·28201314·73). Prednisolone prophylaxis for RAI was highly effective in preventing the progression of GO in patients with pre-existing GO (RR 0·03; 95% CI 0·0020130·24). The use of adjunctive ATD with RAI was not associated with any significant benefit on the course of GO.Conclusion RAI for GD is associated with a small but definite increased risk of development or worsening of Graves’ ophthalmopathy compared with ATDs. Steroid prophylaxis is beneficial for patients with pre-existing GO.



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