Autoimmune thyroid disease: Case reports of two siblings

Abstract

Autoimmune thyroid disease (AITD) is typified by Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) at both ends of the disease spectrum with subclinical thyroid dysfunctions in between. Genetic associations have been described in the pathogenesis of AITD. We describe a case each of GD and HT occurring in two siblings.

INTRODUCTION

Autoimmune thyroid disease (AITD) arises due to an interplay of genetic and environmental factors which cause abnormal regulation of immune tolerance thereby resulting in varying forms of abnormal thyroid function.^[1] The AITD spectrum encompasses Graves’ disease (GD), subclinical thyroid dysfunction and Hashimoto’s thyroiditis (HT) with GD and HT comprising about 5% global incidence of AITD.^[2] Polymorphisms in AITD-related genes have to a large extent described the genetic basis of AITD pathogenesis.^[2]

We report two siblings of South-East Nigerian descent presenting with HT and GD, respectively.

CASE REPORTS

Sibling 1

A 44-year-old female was referred for endocrinology consultation by her general practitioner on account of progressive weight gain, constipation and cold intolerance. Initial thyroid function testing done prior to this referral suggested a possibility of hypothyroidism necessitating the need for further evaluation and the institution of a management plan by an endocrinologist. Physical examination showed an obese female with a weight of 103.5 kg, height of 1.63 m and body mass index (BMI) of 39kg/m². She had normal female hair distribution. Pulse was 72 beats/min, regular with normal pulse volume and blood pressure (BP) 130/86 mmHg. There was no goitre (Figure 1). Other system examinations were essentially normal. Blood was collected for a repeat thyroid function test which showed low free thyroid hormone levels with free thyroxine (T₄) [3.2 pmol/L (10–22 pmol/L)] and free triiodothyronine (T₃) [1.4 pmol/L (3.8–6.0 pmol/L)]. The thyroid-stimulating hormone (TSH) was markedly elevated [100 mIU/L (0.30–4.5 mIU/L)]. The thyroid peroxidase antibody was also elevated [998 IU/mL (0–30 IU/mL)]. A diagnosis of primary hypothyroidism secondary to HT was made, and the patient commenced on thyroxine with doses gradually increased up to 200 µ daily.

Figure 1: Clinical photograph of sibling 1 showing absence of a goiter

Sibling 2

A 32-year-old male presented to a general practitioner after his sister (Sibling 1) was diagnosed with HT. He complained of neck swelling, heat intolerance, palpitations and weight loss. An initial thyroid function testing suggested hyperthyroidism which necessitated referral for endocrinology consultation. Physical examination revealed a young male with a weight of 54 kg, height of 1.69 m and BMI of 18.9 kg/m². Pulse was 120 beats per minute, regular and collapsing with a BP of 134/90 mmHg. There was a palpable diffuse non-tender goitre with thyroid bruit (Figure 2). He had bilateral exophthalmos, lid lag and lid retraction. Repeat thyroid function testing showed markedly elevated free thyroid hormone levels [free T₄ of 68 pmol/L (10–22) and free T₃ of 46.1 pmol/L (3.8–6.0 pmol/L)]. The TSH was low [0.03 mIU/L (0.30–4.5 mIU/L)], while the TSH receptor antibody was elevated [40 IU/L (<1.75 IU/L)]. A diagnosis of primary hyperthyroidism secondary to GD was made, and the patient was started on oral propranolol 40 mg twice-daily and carbimazole which was gradually increased up to a dose of 40 mg daily.

Figure 2: Clinical photograph of sibling 2 showing a diffuse goiter

DISCUSSION

GD and HT are disorders on both extremes of the AITD spectrum with hyperthyroidism and hypothyroidism, respectively, occurring in each case although both conditions may coexist in certain individuals.^[3] In GD, thyroid-stimulating immunoglobulin (TSI) directly stimulates the TSH-receptor (TSH-R) of the thyroid gland resulting in excess production of thyroid hormones. HT involves an initial phase of lymphocytic infiltration of the thyroid follicles followed by the destruction of these follicles. Antibodies against thyroid peroxidase are frequently found but their role in HT pathogenesis is unclear.^[4] The transition from thyrotoxicosis to hypothyroidism and vice versa may be explained by a switch from TSH-R blocking to TSH-R-stimulating antibodies and vice versa.^[3]

There is a female preponderance in both conditions with both genetic and environmental factors playing major roles in their development.^[5,6] Various studies have described certain susceptibility genes for GD and HT with subsequent familial risk.^[7]

The single-nucleotide polymorphism (SNP) in the TSH-R gene contributes to susceptibility to the development of GD.^[8] The homozygous or heterozygous nature of the receptor SNP underlies this risk and is also associated with a defect in the autoimmune regulator gene which results in dysregulation of central immune tolerance and autoimmune effects on thyroid tissue.^[9] Major histocompatibility complex (MHC) classes I and II genes, cytotoxic T-lymphocyte-associated 4 (CTLA4), CD40, CD25, protein tyrosine phosphatase, non-receptor type 22 and the cytokine regulatory genes play roles in the development of both GD and HT.^[2] The SNP in CTLA4 is associated with an increased risk of HT in East Asians and GD in Chinese.^[10] Polymorphisms in CD40 which are expressed on thyroid follicular cells have been shown to correlate with GD.^[11] SNPs in the transcription factor which regulates cytokine signalling pathways have been found to be associated with HT as well as GD.^[12] There are strong associations between these gene polymorphisms and the development of AITD among first-degree relatives.^[13]

We experienced certain limitations in describing these two cases. We could not carry out gene linkage studies on both siblings to attempt to detect any genetic predisposition to AITD. These genetic studies are quite expensive and not readily accessible in many healthcare settings. Another limitation was the inability to carry out thyroid radionuclide imaging for the sibling with GD to demonstrate diffusely increased iodine uptake by the thyroid gland. However, the clinical history, physical examination and laboratory findings were typical of GD through TSI may be falsely positive in cases of thyrotoxicosis not caused by GD.^[14]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.