A Case Study of Subclinical Hyperthyroidism

A 35- year -old female presented with infertility. As part of a work up for infertility, Thyroid Function Tests were performed. Thyroid Stimulating Hormone (TSH) was suppressed whereas the free Thyroxine results (fT4) were normal. These results were consistent with subclinical hyperthyroidism. Further tests were done after 5 months and different results were reported. The levels of TSH had significantly increased while the fT4 levels were normal. The antithyroid peroxidase antibodies were negative (TPOAb) whereas the TSH-receptor auto antibodies (TRAb) had significantly increased. The patient did not complain of any other symptoms apart from infertility. This patient needed in vitro fertilization but before doing so, the levels of TSH needed to be lowered. Thyroxine replacement was started and the target TSH level was achieved after 6 months. Three cycles of in vitro fertilization were done and the patient conceived successfully. During the pregnancy, there was reduced thyroxine replacement and the TSH levels were significantly suppressed. The fT4 levels were within or slightly above the reference levels. At week 31 and week 35, the TSAb levels were significantly increased. The patient was clinically euthyroid for the 39 weeks gestation period and a healthy baby boy was delivered vaginally. Close monitoring of TSH levels post -partum revealed suppression for up to 6 months whereas the fT4 levels gradually increased. During this time, the TRAb levels were consistently high (Deepak, Loh, Mok, & Shyong, 2016). The results suggested development of hyperthyroidism. The patient was put on treatment for thyrotoxicosis and does not plan to get pregnant again. The case clearly demonstrates that autoimmune thyroid diseases can revolve between the two extremes of hyperthyroidism to hypothyroidism (Schimnich, 2016).

The normal levels of TSH are 0.45- 4.5 mIU/L. A reading of (4.0-10.0 mIU/L) is said to be a mild increase whereas any reading that is above 10.0 mIU/L is considered a significant increase. Diagnosis of SCH is made regardless of the degree  of change in TSH levels. The patient level initially was suppressed to 0.04. Five months later, the levels of TSH shot to 28.6 mIU/L showing some inconsistency from suppression to significantly high levels. The initial levels of fT4 were normal at 1.22 ng/dl and they remained at the reference range. Five months later a reading of 0.92 ng/dl was recorded which was still within the reference range. The intention of the clinicians to achieve a TSH levels of <2.5 mIU/L before conception was in line with the optimal range of TSH. TSAb bioassay is used to show the biological activity of TRAb. A reading of 600% at week 31 and 585% at week 35 was significantly high. TPOAb is an important marker of Autoimmune thyroid diseases (Deepak et al.,2016) .

Name of Marker

Normal Range

Optimal Range

TSH

0.45-4.50 mIU/L

1.8 – 3.0

fT4

0.7-1.53 ng/dl

1.0-1.53

TPOAb

< 40 IU/mL

< 40 IU/mL

TRAb

< 1.8 IU/L

< 1.8 IU/L

Table 1

The most probable diagnosis for this patient is Graves disease. Graves disease is an auto immune thyroid disorder that is caused by both genetic factors and environmental factors. The signs and symptoms of the disease are directly or indirectly related to hyperthyroidism (Akaishi Cruz, & Vargas, 2007). Weight loss, sweating, tachycardia, sweating, tremors, and oligomenorrhea are common symptoms of the disease. The disease is also associated with osteoporosis because of release of calcium and phosphorous in urine and stool. Non pitting edema and exophthalmos are two cardinal signs of Graves disease since they do not manifest in other hyperthyroidism related disorders (Akaishi et al,. 2007). Even though the patient denied any other symptoms apart from infertility, the clinical and laboratory results show a possibility of Graves disease. The infertility may have been caused by oligomenorrhea which is directly associated with the disease. The suppression of TSH levels was the first indication of the possibility of Graves disease. In cases when TSH levels are not abnormally low, the T4 levels are normally high which was the case with this patient postpartum. TSH receptor antibodies (TRAb) are known to be the mediators of thyroid stimulation and hence high serum levels of TRAb can be a confirmation of Graves disease which was the case with the patient 5 months after the initial diagnosis of hyperthyroidism. Significant high levels of TSAb in pregnancy and suppressed TSH levels presents a good case for Graves disease.

Being an autoimmune disorder, Graves disease is characterized by production of antibodies to the receptors of Thyroid Stimulating Hormone (TSH). Autoimmunity is mediated by the Band T lymphocytes and the target is the thyroid antigens namely thyrotropin receptor, thyroglobulin, thyroid peroxidase and sodium-iodine symporter (Yeung, 2018). The key auto antigen that is primarily responsible for hyperthyroidism in Graves disease is the thyrotropin receptor. The disease is characterized by a good definition of antibody and thyroid antigen specific immune responses. Thyrotropin receptor antibodies can be transferred passively to the fetus by pregnant women, which can lead to development of hyperthyroidism in the fetus. This can serve as a direct confirmation of existence of hyperthyroidism. In Graves disease, auto antibodies continually stimulate the thyroid gland against thyrotropin receptor which suppresses the secretion of thyrotropin by the pitutitary gland as a result of enhanced secretion of thyroid hormones. Immunoglobulin G1 subclass is responsible for the activity of thyrotropin receptor antibodies. The antibodies responsible for stimulating the thyroid influence the secretion of thyroglobulin and thyroid hormone that is actively mediated by 3,’5’-cyclic adenosine monophosphate (Cyclic AMP). The thyroid stimulating hormones also activate the uptake of iodine, synthesis of proteins and growth of the thyroid gland.

Some thyroid antigens do not play a significant role in the pathophysiology of Graves disease but are used as markers of auto immunity against the thyroid. These are antithyroglobulin, anti-sodium-iodine-symporter and anti thyroid peroxidase. The first histologic abnormality that is witnessed in patients with autoimmune thyroid disease is intrathyroidal lymphocytic infiltration. The thyroid cells are important sources of autoantigens and they also produce molecules that activate T cell adhesion and mediate regulation of cytokines and Fas that actively participate in the immune system. Patients with autoimmunity record levels of CD4 lymphocytes in peripheral blood than in the lymphocytes. The reduction of CD4 lymphocytes can be attributed to enhanced Fas expression in intrathyroidal CD4 T  lyphocytes. Patients with Grave’s disease have been identified with susceptibility genes like PTPN22, CTLA-4, CD40 and TSH receptor. The pathophysiology of ophthalmopathy can be attributed to increased rate of conversion of peripheral blood mononuclear to CD34+ fibrocytes (Afifiyan, Douglas &Hwang, 2010). These cells accumulate in the orbital tissues and are responsible for the production of inflammatory cytokines. Some of these cytokines are TNF-alpha and IL-6. Genome wide studies of Graves disease patients reveal that there are several susceptibility loci associated with the disease and include RNASET2-FGFR1OP-CCR6 region at 6q27, major histocompatibility complex, CTLA4,  intergenic region at 4p14, FCRL3 and also TSH receptor (Chu & Zhao, 2011).

The pathophysiology of Graves Disease relating Thyroid Stimulating Immunoglobulins to hyperthyroidism and ophthalmopathy

Source: Medscape

References

Afifiyan, N.F, Douglas, R.S, Hwang C.J. (2010).  Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 95(1):430-8

Akaishi, P.M , Cruz, A.A, Vargas, M.A, (2007). Association between thyroid autoimmune dysfunction and non-thyroid autoimmune diseases. Ophthal Plast Reconstr Surg. 23(2):104-8.

Chu, X, Pan, C.M, Zhao, S.X. (2011). A genome-wide association study identifies two new risk loci for Graves’ disease. Nat Genet. 43(9):897-901.

Deepak, D.S, Loh, P.T, Mok, S.F and Shyong, E.T. (2016)  An Infertile Patient with Abnormal Thyroid-Stimulating Hormone. Clinical Chemistry 62(10): 1312–1317.

Schimnich, A.A. (2016). An Infertile Patient with Abnormal Thyroid-Stimulating Hormone. Clinical Chemistry 62(10) 1312–1317.

Yeung, S.C. (2018). Graves Disease .Medscape. Retrieved from   https://emedicine.medscape.com/article/120619-overview.