Diseases Associated with Hyperthyroidism

#### **Chapter 5**

## The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes in the Era of Iodine Fortification

*Constance Nontsikelelo Gubu-Ntaba, Vulikhaya Mpumlwana, Nandipha Mizpa Sotobe-Mbana, Martha Mayer, Chukwuma Ogbonna Ekpebegh and Charles Bitamazire Businge*

#### **Abstract**

Graves' disease and nodular toxic thyroid disease are the leading causes of hyperthyroidism. Iodine fortification (IF) among mild-to-moderate iodine deficiency populations is associated with transient increase in incident thyrotoxic nodular disease that may last up to 10 years. A rise in incident Graves' disease and other autoimmune thyroid conditions has also been associated with IF. Epidemiological studies from different geographical settings around the globe suggest increased incidence even among reproductive age groups in affected populations. Recurrent iodine deficiency in iodine replete populations in developed countries may also predispose them to a similar phenomenon. The prevalence and consequences of hyperthyroidism in pregnancy may be higher than previously reported. We intend to describe the aetiopathology and epidemiology of hyperthyroidism, the mechanisms through which hyperthyroidism predisposes to infertility; the impact of hyperthyroidism on fertility treatment, pregnancy in general and among women with infertility; as well as the effects of hyperthyroidism or agents used in the treatment of hyperthyroidism on perinatal outcomes and adult life for those exposed *in utero*.

**Keywords:** hyperthyroidism, infertility, maternal and neonatal outcomes, antithyroid drugs, iodine fortification

#### **1. Introduction**

Thyroid hormones control the metabolism of all nucleated cells and hence are vital for the various processes involved in gametogenesis, fertilisation, embryogenesis, implantation, foetal development and growth *in utero* [1, 2]. Hyperthyroidism is a pathological state characterised by excessive production of thyroid hormones and subsequent elevation of serum levels of thyroxine (T4) and triiodothyronine (T3) and diminution of serum thyroid-stimulating hormone levels [3]. The different aetio-pathological mechanisms leading to hyperthyroidism as well as the various treatment modalities can potentially have a negative impact on male and female fertility, conception, foetal and maternal well-being, as well perinatal and adult life of foetuses exposed *in utero* [2, 4, 5]. Previously hyperthyroidism was reported as having a low prevalence of less than 1%, mainly affecting middle-aged and elderly populations [6]. Recent epidemiological surveys suggest the prevalence rates of up to 1.6% in populations recovering from endemic iodine deficiency following universal iodisation of salt, mainly presenting as toxic thyroid nodules, not only among the elderly but including persons in the age range 20–49 years [7–9]. Pedersen et al. [7] reported an increase of prevalence of hyperthyroidism of 160% in the 20–39 age group in Denmark following food fortification with iodine. In Ghana, following 20 years of universal iodization of salt, Sarfo-Kantanka et al. [8] reported an increase in the incidence of thyroid diseases-related hospital admissions 213 to 538/100,00 admissions. Toxic nodular goitre was the second most common presentation with a percentage of 22.5%, affecting mainly women (female: male ratio of 8.3:1) age range of 27–42 years. This increase in hyperthyroidism following improved access to iodine nutrition although transient but can last up to 10 years [10, 11]. This is followed by a decline in the prevalence of hyperthyroidism in countries that attain and maintain optimal iodine nutrition [7, 9, 12]. It is not clear whether excessive iodine intake in formerly iodine deficiency endemic populations, or recurrent exposure to iodine deficiency in pregnancy like, has been reported in some European countries [13, 14] can lead to prolong the 'transient increase' in hyperthyroidism secondary to iodine fortification. One study from south China reported that pregnancy not only predisposes to hypertrophy of pre-existing nodules, also but to the formation of new nodules with biochemical milieu close to subclinical hyperthyroidism [15].

Some of the increase in prevalence of hyperthyroidism among younger people following fortification of food with iodine has been attributed to thyroid autoimmune disorders. This is in addition to thyroid nodules that were previously reported to be more common among middle aged and the elderly populations that are also increasingly prevalent among people in reproductive years [10, 16]. Graves' disease that has been traditionally reported to be more prevalent in developed iodine-sufficient countries has also been reported in recent studies done in countries recovering from endemic iodine deficiency [17]. This has in part been attributed to an epidemiological transition, or better diagnostic capacity in recent times with many cases remaining undiagnosed in the past.

With an estimated 1.88 billion people at risk of mild-to-moderate iodine deficiency in both developed and developing world and concerted effort to improve iodine nutrition through food fortification [18, 19], the incidence of transient hyperthyroidism at population level secondary to improved iodine nutrition is likely to lead to higher prevalence of hyperthyroidism secondary to nodular thyroid and Graves' disease. Hence, the incidence of hyperthyroidism in developing both developing and developed countries undergoing iodine supplementation due to endemic or recurrent mild-to-moderate iodine deficiency may be higher than previously reported. This not only requires a better understanding of the effect of hyperthyroidism on pregnancy, but also on fertility, and on neonatal and adult life of those exposed to hyperthyroidism and various treatments *in utero*.

In this chapter we intend to

• Describe the aetiopathology and epidemiology of hyperthyroidism

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*


#### **2. Aetiology and pathogenesis**

Hyperthyroidism has a female predilection (sex ratio of 5:1), and a life time risk of 2–5% with a modal age of presentation among females is 20 and 40 years [20]. More than 99% of all patients with hyperthyroidism are as a result of pathological processes within the thyroid gland leading to hyperactivity and excessive secretion of T3 and T4 [20]. Excessive secretion of TSH from the pituitary is an uncommon cause.

Graves' disease, an autoimmune disorder in which stimulatory serum IgG antibodies bind to TSH receptors in the thyroid leading to excessive output of T3 and T4 secretion from the thyroid gland into the circulation, is the leading cause in iodinesufficient regions of the world [20]. Graves' disease tends to affect the young- and middle-aged people [20, 21] and it thought to result from molecular mimicry following infection with bacteria such as *Escherichia coli* and *Yersinia enterocolitica* that possess TSH-binding sites [22]. Other risk factors of Graves' disease include HLA-mediated genetic predisposition as well as smoking [20, 23].

Toxic nodular thyroid lesions are the second most frequent cause of hyperthyroidism and the leading cause in iodine-deficient areas [24]. Previously, toxic thyroid disease associated with iodine deficient was reported to be more prevalent in the elderly [25]. The aetiology of thyroid glandular lesions leading to hyperthyroidism is related to the degree of iodine nutrition of the population [26]. Following the implementation of universal iodization of salt (USI) globally, studies from formerly iodine deficiency endemic areas reported an increased incidence of both Graves' disease and toxic nodular thyroid disease also affecting not only the elderly populations, but also segments of the population in the reproductive age [8, 9, 11]. Like Graves' disease, females are more prone to solitary toxic nodules than males with F:M ratio > 4.8 [8]. Toxic nodular thyroid disease compared to Graves' disease is more prone to resurgence of thyrotoxicosis after achieving euthyroid state with antithyroid drugs [27].

Among populations with low levels of dietary iodine intake, the thyroid gland tries to ensure adequate hormonal production through increased activity of the thyroid follicular cells. Prolongation of this compensatory hyperactivity due to persistent iodine deficiency results into autonomous growth and function of clusters of follicular cells [25]. The increase in dietary iodine intake following the advent of USI implemented in various countries with low-to-moderate severe iodine deficiency results in excessive output of thyroid hormones from the autonomous follicular clusters resulting into nodular toxic thyrotoxicosis [26]. This increased incidence in hyperthyroidism including people of reproductive age requires a concerted effort aimed at preconception diagnosis and management of hyperthyroid disease in people of reproductive age and in early pregnancy so as to mitigate the short- and long-term

foetal, perinatal, maternal and adult life complications associated with uncontrolled hyperthyroidism and its treatment.

Gestational hyperthyroidism also known as gestational transient thyrotoxicosis (GTT) is a transient elevation of serum thyroid hormone levels in pregnant women without evidence of thyroid autoimmunity. GTT affects 1–5% of pregnant women early in pregnancy. This form of thyrotoxicosis usually resolves spontaneously by the end of the first or early second trimester of pregnancy. This is attributed to the physiological elevation of serum HCG, which peaks in the first 8 to 11 weeks of pregnancy, decreasing thereafter, and remaining in plateau up to term [28–31]. GTT has a short and self-limiting course and does not usually require specific treatment. Milder forms are likely to remain unrecognised. Free T4 levels tend to return to normal in the second trimester; hence, supportive management is generally all that is needed [4]. However, in severe form GTT presents as hyperemesis gravidarum, with significant weight loss and thyrotoxicotic features such as tachycardia, hyperreflexia, hand tremors but without goitre or orbitopathy usually associated with Graves' disease [4].

#### **3. Differential diagnosis**

Differential diagnoses of hyperthyroidism are conditions that predispose to thyrotoxicosis without intrinsic hyperactivity of the thyroid gland. These include thyroid pathology that leads to destruction of the follicular cells and consequential release of the preformed T3 and T4 leading to transient thyrotoxicosis. Examples include post-partum thyroiditis, silent thyroiditis and sub-acute painful thyroiditis. Others include iatrogenic T4 administration, medications such as lithium, interferon α and amiodarone, as well as metastatic thyroid carcinoma and thyroid hormone-producing tumours such as struma ovarii [3] and trophoblastic diseases that produce excessive β-HCG that is not only structurally similar to thyroid-stimulating hormone but has accentuated stimulation of the thyroid follicular cells than the normal hCG [32].

#### **4. Hyperthyroidism and reproduction**

Thyroid dysfunction is the most commonly found endocrine problem in females of reproductive age [33]. Hyperthyroidism (both clinical and subclinical) can affect both males and females of reproductive age, by producing variable degrees of gonadal dysfunction [33, 34]. In the general population, it affects 1.5% of reproductive age females and 2.3% of the infertile group [35]. It is associated with infertility, though this is not well established due to limited evidence [36]. According to WHO, infertility is failure to achieve successful pregnancy after 12 months or more of appropriate, timed, unprotected intercourse [37]. Although there is no evidence of improved ovulation rates, treatment of both clinical and subclinical hyperthyroidism is advisable to improve pregnancy adverse outcomes, including early pregnancy loss [35, 36].

#### **4.1 Effect of hyperthyroidism on the hypothalamic, pituitary gonadal axis**

Thyrotoxicosis in females is associated with increased GnRH sensitivity, though most women will still have ovulatory cycles [36, 37]. Other hormonal changes in a female include an increase in the production of sex hormone-binding globulin

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*

(SHBG) and oestrogen with decreased oestrogen clearance. Thyrotoxicosis is also associated with the increased production of androgens such as androstenedione and testosterone that are subsequently converted to estrone [34, 38].

Hyperthyroidism is associated with delayed puberty [32]. Post-puberty hyperthyroidism may be associated with hypomenorrhea, polymenorrhea, oligomenorrhea and hypermenorrhea [34]. These menstrual disturbances are found in about 22% of women with hyperthyroidism compared to 8% of healthy controls [39].

Hyperthyroidism in males is associated with increased incidence of gynecomastia, as well as decreased libido which is attributed to increased levels of free oestrogen [34]. Hyperthyroidism causes oligozoospermia, asthenozoospermia and teratozoospermia, the mechanisms by which these adverse effects come about is poorly understood [40].

#### **4.2 Autoimmune thyroid disease (AITD) and fertility**

Thyroid autoimmune is present in up to 25% of the general population [35]. AITD is associated with poor outcomes pregnancy outcomes among women in reproductive age who are euthyroid, especially those who are undergoing assisted reproduction [35]. The thyroid is affected by autoimmune disease *via* T cells, commonly causing to Graves' disease and Hashimoto's thyroiditis accompanied with hyperthyroidism or hypothyroidism [30]. Most common antibodies include thyroid peroxidase antibodies, thyroglobulin antibodies and thyroid-stimulating hormone receptor antibodies. Thyroid-stimulating antibodies are central to the pathogenesis of Graves' disease, while other antibodies are produced as a response to thyroid injury leading to hypothyroidism. Thyroid-stimulating antibodies have a limited effect on fertility, but have a role in foetal and neonatal hyperthyroidism [30].

The radioactive iodine treatment commonly used for hyperthyroidism, especially Grave's disease does not have an effect on gonadal function but pregnancy should be postponed by at least 6 months after treatment because of teratogenic effect [31, 35].

#### **5. Preconception care**

The best maternal and prenatal outcomes are expected from women who are healthy at the onset of pregnancy [41]. Pregnancy among women with hyperthyroidism faces a two-pronged challenge: potential complications from metabolic derangements secondary to excessive thyroid hormones and circulating auto-antibodies among women with Graves' disease; and the adverse effects of the varied treatment remedies aimed at the control thyroid function close to the normal state [4]. The principles of preconception care for women with hyperthyroidism are to use effective contraception until the patient achieves a sustained euthyroid state [42]. This will reduce the complications associated with the deranged metabolic state due to excessive thyroid hormones in the circulation.

In order to reduce the risk of teratogenicity, women who have attained a euthyroid state preconceptionally when treated with carbimazole or methimazole should be switched to propylthiouracil till a stable euthyroid state is maintained before attempting to conceive [43]. Treatment with propylthiouracil should be continued until organogenesis is deemed complete at the end of the first trimester.

Since pregnancy is associated with diminution of cell-mediated immunity and reduced risk of relapse, an alternative strategy for euthyroid women with Graves' disease with TSH receptor antibodies (TRab) below cut-off level, on minimum doses of antithyroid drugs is to withhold the antithyroid drugs at the inception of pregnancy. Then, they are to be followed closely with prompt reinstatement of treatment in case of relapse [43, 44]. Women who still desire pregnancy but are at high risk of relapse due to high-circulating levels of TRab titres should be counselled for the option of total thyroidectomy and thyroid hormone replacement [44].

#### **6. Thyroid physiology in pregnancy**

The thyroid gland produces T3 and T4 which are essential for normal maternal and foetal metabolism. The hypothalamic-pituitary-thyroid axis is important for this control [45]. Increase in oestrogen concentration in pregnancy results in elevated hepatic synthesis of thyroid-binding globulin (TBG) necessitating increased T3and T4 output from the thyroid gland. This coupled with relative iodine deficiency due to increased maternal glomerular excretion, and transplacental transfer of iodine to the foetus combined with high levels of HCG leads to maternal thyroid hyperstimulation [46]. This increases the serum T4 and T3 levels between 6 and 12 weeks of gestation reaching a plateau at 20 weeks which through negative feedback reduces TSH secretion from the pituitary [46, 47]. In early pregnancy, there is transplacental transfer of maternal T4 but not TSH which is essential for foetal metabolism and normal neurological development. In the second trimester, there is placental metabolism of maternal thyroid hormones and the foetal thyroid takes over thyroid hormone synthesis using iodine obtained through transplacental transfer from the mother [29].

The normal range of thyroid function tests in pregnancy varies according to iodine dietary content and ethnicity, and fluctuations across the trimesters of pregnancy [48]. Total T4 (tT4) has been found to be more reliable for measurement during pregnancy compared with fT3 and fT4. To adjust for the general increase of tT4 in pregnancy compared to non-pregnancy state, it is recommended that the levels should be multiplied by 1.5. As an option fT4 index may also be used in pregnancy, as it corrects tT4 according to the TBG levels [48].

#### **6.1 Hyperthyroidism and interpretation of results in pregnancy**

HCG, which is structurally similar to TSH molecule, has a weak stimulatory effect on the thyroid cells resulting in elevated T4 and T3 [28, 29]. A negative feedback effect of the elevated thyroid hormones on the anterior pituitary results in low levels of TSH [48]. This reduction is estimated to be about 0.1–0.2 mU/L for the lower limit and 0.5–1.0 mU/L for the upper limit compared to non-pregnant state [41]. HCG levels decrease in the second trimester; therefore, TSH level rises again [48]. The use of trimester-specific TSH reference values is necessary in pregnancy due to these physiological changes that result in modification of the normal reference ranges of serum thyroid-stimulating hormone**.** Free serum T4 (FT4) estimates are unreliable during pregnancy compared to TSH that remains sensitive in pregnancy despite the effects of HCG (human chorionic gonadotropin) (**Table 1**) [41].

#### **6.2 Clinical features of hyperthyroidism pregnancy**

The clinical features of hyperthyroidism overlap with those of pregnancy and hence may make diagnosis difficult especially for a patient who develops incident *The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*


#### **Table 1.**

*Comparison of serum thyroid hormone levels in pregnancy and non-pregnant state.*


#### **Figure 1.**

*Biochemical features of gestational thyrotoxicosis, Graves' disease and nodular thyroid disease.*

hyperthyroidism in the first trimester of pregnancy [49]. These include palpitations dyspnoea, fatigue, sweating and haemic murmurs. If these features become severe in addition to nervousness and hyperactivity, it is prudent to exclude thyrotoxicosis with its underlying cause.

Although graves' disease has traditionally been reported in the young adults, and nodular toxic thyrotoxicosis in older people, it is worthwhile to consider both conditions in addition to gestational thyrotoxicosis when presented with a symptomatic pregnant woman [10, 16]. This is informed by the increased prevalence of both autoimmune and nodular thyroid disease with iodine fortification coupled with recurrent migration within and between countries and continents [15].

Some features that can help distinguish between the three commonest underlying causes of thyrotoxicosis in pregnancy are shown in **Figure 1** and **Table 2** [50–52].

#### **6.3 Effect of pregnancy on the common underlying entities of thyrotoxicosis**

#### *6.3.1 GTT*

Since gestational transient thyrotoxicosis is caused by excessive hCG or in heritable TSHR hypersensitivity to hCG, GTT will be self-limiting and most patients will revert to normal thyroid function after the first trimester especially by about 20-week gestation following the natural reduction in serum hCG [51]. However, thyrotoxicosis may persist beyond the first trimester among women with hyper-placentosis such as


#### **Table 2.**

*Differentiating clinical features of Graves' disease, gestational thyrotoxicosis and toxic nodular disease.*

in multiple pregnancy or among women with heritable TSHR hypersensitivity to hCG. In these patients, toxic nodular goitre need be excluded.

#### *6.3.2 Graves' disease*

Due to the diminishing levels of cell-mediated immunity as pregnancy progresses, serum levels of TRab tend to reduce in the second and third trimester with the consequent reduction in levels of T3 and T4 as well as the symptoms of Graves' disease [29].

#### *6.3.3 Toxic thyroid nodules*

Pregnancy is associated with increase in the size and number of thyroid nodules especially among women of higher parity [15]. This may potentially increase the severity of thyrotoxicosis and the necessity for treatment or increase in doses of ATD or lead to surgical intervention.

#### **6.4 Impact of thyrotoxicosis on pregnancy**

Without optimum maternal treatment, hyperthyroidism in pregnancy is associated with maternal and foetal adverse outcomes. This could be secondary to the high metabolic state and specific pathological processes, and ATD [29, 41].

#### *6.4.1 Impact on maternal health*

Severe GTT may be associated with hyperemesis gravidarum that in addition to features of thyrotoxicosis will present with weight loss of ≥5%, dehydration and ketonuria [4]. Rather than being a direct complication this may be due to the shared mechanism of high levels or hypersensitivity to circulating hCG.

Maternal nodular goitre can lead to tracheal obstruction. Irrespective of the primary cause, high levels of thyroid hormones T3 and T4 may predispose to maternal arrythmias and cardiac failure, or thyroid storm, miscarriage, abruptio placenta and preeclampsia. Elevated TRAb preconception is a prognostic of risk for relapse of GD, failing ATD or cessation [53].

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*

#### *6.4.2 Maternal complications*

Maternal complications of hyperthyroidism include preeclampsia, abruptio placenta, incident diabetes mellitus, thyroid storm, and arrhythmia, congestive heart failure, and cardiovascular disease [4, 41]. In a recent systematic review and metaanalysis, Alves et al. [5] found that the treatment of hyperthyroidism was associated with reduced risk of abruptio placentae, gestational diabetes mellitus and postpartum haemorrhage.

#### **6.5 Management of hyperthyroidism in pregnancy**

Optimum management of hyperthyroidism in pregnancy necessitated a multidisciplinary team comprising of an obstetrician, maternal foetal medicine specialist and paediatric endocrinologist, and a neonatologist is necessary, and sometimes adult and paediatric critical care specialists if complications arise [29]. The aim of treatment is to achieve near-euthyroid state without causing adverse effects to the mother and the foetus.

Challenges of treatment include the following:


#### *6.5.1 Management of GTT*

GTT is usually self-limiting hence symptomatic treatment is usually recommended [49]. If symptoms persist beyond 16 weeks gestation into the second half of pregnancy, or is severe enough to require ATD, the patient should be re-valuated and screened for GD, toxic adenoma or TMN goitre.

#### *6.5.2 Management of thyrotoxicosis among women with GD, toxic adenoma and multinodular goitre in pregnancy*

The management includes administration of ATD, beta-blockers and supportive treatment as needed. The mechanism of action of thionamides is to block the synthesis of thyroid hormones; in addition, PTU blocks the peripheral conversion of T4 to more potent T3 [55]. The aim of ATD therapy is to maintain thyroid hormones levels at the upper point of the normal range with the minimum possible dosages of the drugs. PTU should be used in the first trimester as recommended and then later substituted with methimazole in the second trimester to avoid hepatotoxicity associated with it. Adjunctive treatment with beta-adrenergic blockers may be used to reduce tachycardia, palpitations and tremors. Propranolol 20 to 40 mg orally every 8 to 12 hours may be used while awaiting response to the antithyroid medications [4]. Antithyroid

#### *Hyperthyroidism - Recent Updates*

medications can and should be tapered as pregnancy progresses [56]. When serum TSH rises to detectable level, this is an indication to reduce ATD.

In patients in with GD in which ATD is discontinued in the third trimester, close monitoring should be done in the postpartum period due to high risk of relapse [56]. The indications for thyroidectomy include severe thyrotoxic orbitopathy, high TRab titres post-radioiodine therapy in GD, obstructive goitre and adverse drug reaction [54].

Since the risk of recurrence of toxic multinodular goitre treated with ATD is more than 95%, patients with thyrotoxic multinodular disease treated with ATD during pregnancy should be considered for thyroidectomy in the in the postpartum period [27].

#### **7. Maternal hyperthyroidism and the foetus**

The foetal thyroid gland develops 24-days post-conception and is capable of taking up iodine from 10 to 11 weeks. Foetal thyroid hormone production is controlled by the foetal hypothalamo-pituitary axis beginning 20 weeks after conception. Foetal levels of TSH, T4 and T3 reach adult levels by 36 weeks [55]. Transplacental passage of maternal thyroid-stimulating antibodies or ATD, both of which may disrupt foetal thyroid function have an effect on foetal prognosis [29].

#### **7.1 Effect of TRab on the foetus**

The foetus may develop thyrotoxicosis secondary to the maternal receptor antibodies, which having crossed the placenta stimulates the adenylate cyclase in foetal thyrocytes. The foetus of untreated or mothers with poorly controlled GD disease may be complicated by foetal goitre, intrauterine growth retardation, low birth weight and preterm birth or foetal death may occur [4]. These foetal complications have also been observed in pregnancies of some women with Graves' disease that became euthyroid after surgical or radioiodine treatment that remained with high-serum thyroid receptor antibodies [57]. The detection of TRAbs in pregnancy should result in the foetus being considered at risk of developing thyrotoxicosis and monitored accordingly [58].

#### **7.2 Effects of maternal ATD therapy on the foetal thyroid**

All available ATDs (MMI, CM, PTU) cross the placenta and therefore have the potential to cause foetal hypothyroidism [4]. Early exposure in pregnancy to ATD has been associated with birth defects [4]. PTU is associated with less common and less severe teratogenicity than MMI (**Table 3**) [59]. ATD doses necessary to maintain maternal FT4 in the upper normal to mildly thyrotoxic range are associated with normal foetal thyroid function. Higher doses of ATD predispose to foetal hypothyroidism and goitre [4]. Therefore, it is recommended the lowest effective dose of MMI or PTU to maintain maternal serum FT4/TT4 at or moderately above the upper limit of the reference range should be used.

The 'Block' and 'replace' treatment method with ATD and levothyroxine (LT4) should be avoided in pregnancy because the transplacental passage of ATD is high, whereas it is negligible for thyroid hormones; hence, addition of LT4 will not protect the foetus from ATD-induced hypothyroidism [60, 61].

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*


#### **Table 3.**

*Birth defects associated with ATDs.*

#### **7.3 Foetal ultrasound**

Mothers with positive Trab should be referred to a maternal foetal medicine specialist for foetal surveillance. This includes foetal ultrasound in the first trimester for dating and nuchal translucency (NT scan), foetal anomaly scan at 18–22 weeks and 2–3 weekly scans to screen for adverse effects of TRab and ATD. Ultrasound features of foetal hyperthyroidism include goitre detected as a solid hyperechogenic vascular neck mass [60], tachycardia, hydrops, polyhydramnios and risk of premature rupture of membranes and preterm labour and foetal growth restriction [4].

Foetal hypothyroidism may be diagnosed by the presence of a large goitre, polyhydramnios and bradycardia. Demonstration of peripheral blood flow on foetal thyroid Doppler ultrasound differentiates goitre due to foetal hypothyroidism from that due to foetal hyperthyroidism, which has both peripheral and central blood flow [62].

#### **7.4 Management of foetal complications**

The mainstay of treatment of foetal GD secondary to transplacental maternal TRab regardless of maternal thyroid state is the administration of ATD to the mother and monitoring of reduction of foetal goitre and foetal heart rate. In case maternal hypothyroidism ensues, this is managed with levothyroxine replacement [41].

The approach to foetal hypothyroidism secondary to maternal ATD is to reduce the dose and aim to keep the T4 levels closer to the upper limit of normal [52]. In rare cases where hypothyroidism does not resolve following reduction of maternal ATD doses, invasive therapy with intra-amniotic levothyroxine at a dose of 10mcg/kg/week for several weeks can be given [52].

When foetal goitre persists to time of delivery a planned elective caesarean section should be performed with EX-Utero Intrapartum Treatment (EXIT) procedure to secure the airway with intubation while still maintaining placental circulation [60].

#### **8. Children Born to Mothers with Hyperthyroidism**

Since GTT is usually self-limiting [29], children born to mothers with GTT are expected to be healthy at birth. Those born to mothers with Graves and nodular

thyrotoxicosis requiring treatment may present with complications secondary to transplacental transfer of ATD [63]. Antithyroid drugs are also transferred into the breast milk and this has been previously thought to put the nursing neonate at risk of hypothyroidism. However, several studies evaluate thyroid function in infants whose mothers breastfed while taking PTU or MMI failed to detect the adverse effects on the newborn [64]. Continuation of breastfeeding is generally now considered safe and should be encouraged in hyperthyroid mothers taking ATD.

About 1–2% of neonates born to mothers with GD develop neonatal hyperthyroidism although some have reported an incidence as high as 5% [65, 66]. Neonatal thyrotoxicosis carries significant morbidity and mortality. In most cases, neonatal thyrotoxicosis is transient and results from the transplacental passage of maternal stimulating TSH receptor antibodies (TRAb) [66, 67]. TRAb may also be transferred to the baby by way of breastmilk and cause neonatal hyperthyroidism, which requires treatment even if the mother is euthyroid [67].

All infants born to mothers with a history of Graves' disease should undergo careful examination and monitoring to screen for the development of clinical hyperthyroidism and serious complications associated with it [29]. Neonates born to mothers with Graves' disease with good control on ATD may not have obvious symptoms of hyperthyroidism at birth, which may result in delayed diagnosis and complications [4]. Neonates born to mothers who tested negative for TRAb during the second half of gestation or those that exhibited absence of TRAb in the cord blood are unlikely to develop hyperthyroidism and are considered low-risk patients [68]. However, all neonates of mothers with hyperthyroidism require a focused assessment at birth for potential complications.

#### **8.1 Clinical presentation of neonatal hyperthyroidism**

The time of onset and severity of symptoms of hyperthyroidism are variable. Neonates born to mothers who had high TRAb levels (more than three times the upper normal value) and who were not treated with ATDs can exhibit overt hyperthyroidism at birth, while neonates born to mothers treated with ATDs or neonates who receive maternal thyroid receptor blocking antibodies may have normal thyroid function or present with hypothyroidism at birth [69, 70]. Some neonates of mothers with GD on antithyroid medication may be born with the features of hypothyroidism and later after about 2–5 days of life may show signs of hyperthyroidism following subsequent metabolism and excretion of maternal ATDs from their circulation [71].

The neonatal hyperthyroidism may present with a thyroid storm marked by tachycardia, hypertension, hyperthermia, tremors, irritability, restlessness, sweating, difficulty in sleeping, tachypnoea, arrhythmia, supraventricular tachycardia and cardiac failure [72]. Neonates with thyrotoxicosis and cardiac failure have a high mortality rate of up to 20% if not timely and adequately treated [73].

Maternal TRab may remain in the infant circulation for from a month up to 3 months, most neonates with congenital hyperthyroidism respond to ATD therapy within 1–2 months [74]. However, there might be some long-term adverse effects on cognitive development even with the prompt treatment.

Others may present with features such as frontal bossing, triangular face, periorbital oedema, goitre, hyperactivity, failure to thrive despite excessive appetite, reduction in the subcutaneous adipose tissue [68]. The neonate may also present with non-specific clinical features such as diarrhoea, vomiting, fever, sweating, pulmonary hypertension, chylothorax, jaundice, hepatosplenomegaly, prolonged acrocyanosis and sialadenitis. Premature closure of cranial sutures (craniosynostosis) and subsequent microcephaly may be noted in severely affected infants [75].

#### **8.2 Laboratory tests for neonates with hyperthyroidism**

It is recommended that neonates born to mothers with TRAb antibodies as well as neonates with a known family history of genetic congenital hyperthyroidism should have their cord blood tested for the TRAb between days 3 and 5 after birth, then at 2 weeks and 3 months [68, 76]. Thyroid function tests performed on the cord blood before the third day of life in neonates tend to reflect intrauterine foetal thyroid status and are poor predictors of neonatal hyperthyroidism. Thyroid function tests start showing biochemical picture in the neonates with hyperthyroidism between days 3 and 15 following birth [77].

High-risk infants with normal initial testing should have repeat blood workup at days 10–14 days of life or when symptoms appear. Hyperthyroidism in the newborn is suggested by high T4 and T3 levels with low TSH (<0.9 mlU/L) [66]. Additional investigations to check for other organ malfunction include AST, ALT and direct bilirubin, blood sugar, and platelets, cardiac and thyroid ultrasonography as well as wrist and hand X-ray for assessment of bone maturation [66].

#### **8.3 Management of neonates with hyperthyroidism**

Treatment should be promptly initiated upon clinical and biochemical diagnosis of neonatal hyperthyroidism [76]. Early and appropriate treatment is necessary in order to reduce the risk of heart failure in the acute phase. Adequate hydration should be maintained and airway, breathing and circulatory support should be provided if required [71]. Pharmacological treatment includes adrenergic blockage, inhibition thyroid hormone synthesis, release and peripheral conversion, reduction of preload afterload and regulation of cardiac rhythm and other supportive treatment (**Table 4**) [71]. Infants with persistent hyperthyroidism despite adequate medical treatment may require thyroidectomy [66].

#### **8.4 Pathogenesis of congenital hypothyroidism among neonates born to mothers with hyperthyroidism**

Some neonates of mothers with hyperthyroidism may be born with congenital hypothyroidism which may be central or primary. Primary neonatal hypothyroidism may occur among children born to mothers on ATD, or Graves' disease secondary to TSHR blocking antibodies transfer across the placenta, which directly suppresses T3 and T4 production in the foetal thyroid (**Table 5**). Among these patient's neonatal hypothyroidism tends to be transient due to the clearance of the ATD and antibodies from the neonatal circulation; hence, they may not require treatment [78].

Central hypothyroidism arises from downregulation and delayed maturity of the foetal pituitary due to excessive production of thyroid hormones following foetal thyroid stimulation by maternal TRSAB. This tends to be transient in about 70% of the neonates; however, in 30% it may persist requiring lifelong treatment with levothyroxine [66, 79].


#### **Table 4.**

*Treatment options for neonates with congenital hyperthyroidism.*


**Table 5.**

*Biochemical features of central and primary neonatal hypothyroidism.*

#### *8.4.1 Clinical features of neonates with congenital hypothyroidism*

Most neonates with congenital hypothyroidism may be asymptomatic; however, symptoms include decreased motor activity, longer spells of sleeping, feeding difficulties, horse cry and prolonged jaundice. The physical examination may reveal enlarged fontanelles, macroglossia, hypotonia, rounded abdomen, umbilical hernia and myxoedema [80].

#### *8.4.2 Management of neonates with congenital hypothyroidism*

The recommended treatment should be L-T4 which should be initiated within the first 2 weeks of life at a dose of 10–15 mcg/kg/day according to severity of the disease and dose adjusted according to fT4 and TSH levels [81]. Close follow-up of 1–2 weeks is necessary till TSH levels are established then 1–3 months in the first year and then 2–4 months in the first 3 years. The target is to keep TSH levels within the normal limits according to age and fT4 levels in the upper half of the normal range [81].

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*

#### **9. Postpartum thyroiditis and depression**

Postpartum thyroiditis is an autoimmune destructive inflammation of the thyroid gland that manifests within the first 12 months after delivery or miscarriage [82]. A fifth to one quarter of the patients present with the classic biphasic nature of thyrotoxicosis presenting within the first 1–4 months after delivery followed by hypothyroid state in the next 4–8 months. Another quarter present only with thyrotoxicosis, about 50% only with hypothyroid phases [41, 83]. About 80–85% revert to euthyroid state, the rest remaining hypothyroid [41, 83]. While postpartum thyroiditis is associated with a wide range of somatic and psychic symptoms, depression has been more associated with the hypothyroid phase, while anxiety and hyperactivity are more common in the thyrotoxicosis phase of this disease [83]. This may explain the conflicting results reported by different studies that sought to establish the relationship between postpartum thyroiditis and postpartum depression [84, 85] that may have had participants with differing phases of postpartum thyroiditis. Anticipation of the possible incidence of postpartum depression during the hypothyroid phase will help plan appropriate follow-up with consequent early diagnosis and management of women at risk of postpartum depression secondary to postpartum thyroiditis.

An increased incidence of thyroid autoimmunity has been reported following iodine supplementation among populations with mild-to-moderate iodine deficiency [7, 8]. The physiological diminution of cell-mediated immunity during pregnancy may mask the autoimmune thyroiditis, which may manifest as postpartum thyroiditis and with features of depression several months postpartum well past the puerperium period [4, 86]. Hence, it may be prudent to increase surveillance for postpartum thyroiditis and postpartum depression in populations undergoing iodine supplementation due to endemic mild-to-moderate iodine deficiency.

#### **10. Conclusion**

Although hyperthyroidism has limited impact on fecundity, if undiagnosed or not effectively controlled, it can greatly reduce fecundability for both fertile women and those on fertility treatment through early pregnancy losses and iatrogenic preterm delivery that may accompany maternal complications. The transient increase in hyperthyroidism secondary to iodine fortification is associated with higher incidence non-toxic and toxic thyroid nodules among women in later half of reproductive age and Graves' disease among younger women. This may not only increase the incidence of perinatal, congenital and behavioural complications associated with *in utero* exposure to ATD and TRabs, but also maternal mental and cardiovascular complications. This calls for more studies to further elucidate the epidemiology of hyperthyroidism and other thyroid disease especially in populations with recurrent waves of recurrent iodine deficiency or excess with concurrent iodine fortification as well as increased vigilance during prenatal and postnatal care. Poorly controlled hyperthyroidism in pregnancy is associated with maternal morbidity and mortality. Long follow-up of children born to mothers with hyperthyroidism is crucial as they may present with neurocognitive disorders.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Constance Nontsikelelo Gubu-Ntaba1,2, Vulikhaya Mpumlwana1,2, Nandipha Mizpa Sotobe-Mbana1,3, Martha Mayer1,3, Chukwuma Ogbonna Ekpebegh1,4 and Charles Bitamazire Businge1,2\*

1 Walter Sisulu University, Mthatha, South Africa

2 Department of Obstetrics and Gynaecology, Nelson Mandela Academic Hospital, Mthatha, Eastern Cape, South Africa

3 Department of Paediatrics, Nelson Mandela Academic Hospital, Mthatha, Eastern Cape, South Africa

4 Department of Internal Medicine, Nelson Mandela Academic Hospital, Mthatha, Eastern Cape, South Africa

\*Address all correspondence to: cbusingae@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*

#### **References**

[1] Yen PM. Physiological and molecular basis of thyroid hormone action. Physiological Reviews. 2001;**81**(3): 1097-1126

[2] Mintziori G, Kita M, Duntas L, Goulis DG. Consequences of hyperthyroidism in male and female fertility: Pathophysiology and current management. Journal of Endocrinological Investigation. 2016;**39**: 849-853

[3] De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;**388** (10047):906-918

[4] Moleti M, Di Mauro M, Sturniolo G, Russo M, Vermiglio F. Hyperthyroidism in the pregnant woman: Maternal and fetal aspects. Journal of Clinical & Translational Endocrinology. 2019;**12** (16):100190. DOI: 10.1016/j. jcte.2019.100190

[5] Alves Junior JM, Bernardo WM, Ward LS, Villagelin D. Effect of hyperthyroidism control during pregnancy on maternal and Fetal outcome: A systematic review and metaanalysis. Frontiers in Endocrinology. 2022;**13**:800257. DOI: 10.3389/ fendo.2022.800257

[6] Laurberg P, Cerqueira C, Ovesen L, Rasmussen LB, Perrild H, Andersen S, et al. Iodine intake as a determinant of thyroid disorders in populations. Best Practice & Research. Clinical Endocrinology & Metabolism. 2010;**24** (1):13-27

[7] Pedersen IB, Laurberg P, Knudsen N, Jorgensen T, Perrild H, Ovesen L, et al. Increase in incidence of hyperthyroidism predominantly occurs in young people after iodine fortification of salt in Denmark. The Journal of Clinical

Endocrinology & Metabolism. 2006;**91** (10):3830-3834

[8] Sarfo-Kantanka O, Kyei I, Sarfo FS, Ansah EO. Thyroid disorders in Central Ghana: The influence of 20 years of iodization. Journal of Thyroid Research. 2017;**2017**:7843972. DOI: 10.1155/2017/ 7843972

[9] Wang C, Li Y, Teng D, Shi X, Ba J, Chen B, et al. Hyperthyroidism prevalence in China after universal salt iodization. Frontiers in Endocrinology. 2021;**12**:651534. DOI: 10.3389/ fendo.2021.651534

[10] Laurberg P, Bülow Pedersen I, Knudsen N, Ovesen L, Andersen S. Environmental iodine intake affects the type of nonmalignant thyroid disease. Thyroid. 2001;**11**(5):457-469

[11] Petersen M, Knudsen N, Carlé A, Andersen S, Jørgensen T, Perrild H, et al. Thyrotoxicosis after iodine fortification: A 21-year Danish population-based study. Clinical Endocrinology. 2018;**89** (3):360-366

[12] Shan Z, Chen L, Lian X, Liu C, Shi B, Shi L, et al. Iodine status and prevalence of thyroid disorders after introduction of mandatory universal salt iodization for 16 years in China: A cross-sectional study in 10 cities. Thyroid. 2016;**26**(8):1125- 1130

[13] Lazarus JH. Iodine status in Europe in 2014. European Thyroid Journal. 2014;**3**:3-6

[14] Zimmermann MB, Gizak M, Abbott K, Andersson M, Lazarus JH. Iodine deficiency in pregnant women in Europe. The Lancet Diabetes and Endocrinology. 2015;**3**:672-674

[15] Kung AW, Chau MT, Lao TT, Tam SC, Low LC. The effect of pregnancy on thyroid nodule formation. The Journal of Clinical Endocrinology and Metabolism. 2002;**87**:1010-1014

[16] Vitti P, Rago T, Tonacchera M, Pinchera A. Toxic multinodular goiter in the elderly. Journal of Endocrinological Investigation. 2002;**25**:16-18

[17] Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nature Reviews. Endocrinology. 2018;**14** (5):301-316

[18] Andersson M, Karumbunathan V, Zimmermann MB. Global iodine status in 2011 and trends over the past decade. The Journal of Nutrition. 2012;**142**(4): 744-750

[19] Volzke H, Erlund I, Hubalewska-Dydejczyk A, Ittermann T, Peeters RP, Rayman M, et al. How do we improve the impact of iodine deficiency disorders prevention in Europe and beyond? European Thyroid Journal. 2018;**7**(4): 193-200

[20] Howlett TA, Levy MJ. Endocrine disease. In: Kumar P, Clark M, editors. Kumar and Clark's Clinical Medicine. 7th ed. Vol. 18. Edinburgh. London. New York. Oxford. Philadelphia. St Louis. Sydney. Toronto: Saunders Elsevier; 2009. p. 9631027

[21] Nystrom HF, Jansson S, Berg G. Incidence rate and clinical features of hyperthyroidism in a long-term iodine sufficient area of Sweden (Gothenburg) 2003-2005. Clinical Endocrinology. 2013;**78**:768-776

[22] Marino M, Latrofa F, Menconi F, Chiovato L, Vitti P. Role of genetic and non-genetic factors in the etiology of

Graves' disease. Journal of Endocrinological Investigation. 2015;**38**: 283-294

[23] Wiersinga WM. Smoking and thyroid. Clinical Endocrinology. 2013;**79**: 145-151

[24] Laurberg P, Nohr SB, Pedersen KM, et al. Thyroid disorders in mild iodine deficiency. Thyroid. 2000;**10**:951-963

[25] Laurberg P, Cerqueira C, Ovesen L, Rasmussen LB, Perrild H, Andersen S, et al. Iodine intake as a determinant of thyroid disorders in populations. Best Practice & Research. Clinical Endocrinology & Metabolism. 2010;**24** (1):13-27

[26] Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. The Lancet Diabetes and Endocrinology. 2015;**3**(4):286-295

[27] van Soestbergen MJ, van der Vijver JC, Graafland AD. Recurrence of hyperthyroidism in multinodular goiter after long-term drug therapy: A comparison with graves' disease. Journal of Endocrinological Investigation. 1992; **15**:797-800

[28] Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid. 1995;**5**(5):425- 434. DOI: 10.1089/thy.1995.5.425

[29] Nguyen CT, Sasso EB, Barton L, Mestman JH. Graves' hyperthyroidism in pregnancy: A clinical review. Clinical Diabetes and Endocrinology. 2018;**4**:4. DOI: 10.1186/s40842-018-0054-7

[30] Wang JW, Liao XX, Li T. Thyroid autoimmunity in adverse fertility and pregnancy outcomes: Timing of assisted reproductive technology in AITD women: Journal of translational. Internal Medicine. 2021;**9**(2):76-83

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*

[31] Davis LB, Lathi RB, Dahan MH. The effect of infertility medication on thyroid function in hypothyroid women who conceive. Thyroid. 2007;**17**:7737

[32] Pereira JVB, Lim T. Hyperthyroidism in gestational trophoblastic disease – A literature review. Thyroid Research. 2021;**14**(1): 1-7

[33] Karaca N, Akpak YM. Thyroid disorders and fertility: International. Journal of Research in Medical Sciences. 2015;**3**(6):1299-1304

[34] Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocrine Reviews. 2010;**31**(5):702-755

[35] Jeffereys A, Vanderpump M, Yasmin E. Thyroid dysfunction and reproductive health. The Obstetrician and Gynaecologist. 2015;**17**:39-45

[36] Unuane D, Velkeiers B. Impact of thyroid disease on fertility and assisted conception. Best Practice and Research Clinical Endocrinology and Metabolism. 2020;**34**:101378

[37] Zegers-Hochschild F, Adamson GD, de Mouzonj I, Mansour R, Nygraw K, Sullivan B, et al. ICMART/WHO revised glossary on ART terminology. Human Reproduction. 2009;**24**:2683-2687

[38] Sturgis SH, Lerman J, Stanbury JB. The menstrual pattern in thyroid disease. The Journal of Chinese Endocrinology & Metabolism. 1952;**12**:846-855

[39] Joshi JV, Bhandarkar SD, Chadha M, et al. Menstrual irregularities and lactation failure may precede thyroid dysfunction or goitre. Journal of Postgraduate Medicine. 1993;**39**: 137-141

[40] La Vignersa S, Vita R. Thyroid dysfunction and semen quality. International Journal of Immunopathology and Pharmacology. 2018;**32**:1-5

[41] Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;**27**:315-389

[42] Gheorghiu ML, Bors RG, Gheorghisan-Galateanu AA, Pop AL, Cretoiu D, Varlas VN. Hyperthyroidism in pregnancy: The delicate balance between too much or too little antithyroid drug. Journal of Clinical Medicine. 2021;**10**(16):3742. DOI: 10.3390/jcm10163742

[43] Okosieme OE, Khan I, Taylor PN. Preconception management of thyroid dysfunction. Clinical Endocrinology. 2018;**89**(3):269-279. DOI: 10.1111/ cen.13731

[44] Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;**26**:1343-1421

[45] Wright H, Williams D. Thyrotoxicosis in pregnancy. Fetal and Maternal Medicine Review. 2013;**24**(2): 108-128

[46] Donna MN, Cootauco AC, Burrow G. Thyroid disease in pregnancy. Clinics in Perinatology. 2007;**34**:543-557

[47] Nisha Nathan MD, Shannon D, Sullivan. Thyroid disorders during pregnancy. Endocrinology and Metabolism Clinics of North America. 2014;**43**:573-597

[48] Cotzias C, Wong SJ, Taylor E, Seed P, Girling J. A study to establish gestation-specific reference intervals for thyroid function tests in normal singleton pregnancy. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2008;**137**(1): 61-66

[49] Cooper DS, Lauberg P. Hyperthyroidism in pregnancy. The Lancet Diabetes and Endocrinology. 2013;**3**:238-249

[50] Laurberg P, Vestergaard H, Nielsen S, Christensen SE, Seefeldt T, Helleberg K, et al. Sources of circulating 3,5,3<sup>0</sup> triiodothyronine in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases. The Journal of Clinical Endocrinology and Metabolism. 2007;**92**(6):2149-2156

[51] Goldman AM, Mestman JH. Transient non-autoimmune hyperthyroidism of early pregnancy. Journal of Thyroid Research. 2011;**2011**: 142413

[52] Mestman JH. Hyperthyroidism in pregnancy. Current Opinion in Endocrinology, Diabetes, and Obesity. 2012;**19**:394-401

[53] Gargallo-Fernández M. Hyperthyroidism and pregnancy. Endocrinología y Nutrición. 2013;**60**: 535-543

[54] Negro R, Mestman JH. Thyroid disease in pregnancy. Best Practice & Research. Clinical Endocrinology & Metabolism. 2011;**25**(6):927-943

[55] Polak M, Luton D. Fetal thyroïdology. *Best practice & research*. Clinical Endocrinology & Metabolism. 2014;**28**(2):161-173. DOI: 10.1016/j. beem.2013.04.013

[56] Krassas G, Karras SN, Pontikides N. Thyroid diseases during pregnancy: A number of important issues. Hormones (Athens, Greece). 2015;**14**(1):59-69

[57] van Dijk MM, Smits IH, Fliers E, Bisschop PH. Maternal thyrotropin receptor antibody concentration and the risk of fetal and neonatal thyrotoxicosis: A systematic review. Thyroid. 2018;**28** (2):257-264

[58] Abeillon-du Payrat J, Chikh K, Bossard N, Bretones P, Gaucherand P, Claris O, et al. Predictive value of maternal second-generation thyroidbinding inhibitory immunoglobulin assay for neonatal autoimmune hyperthyroidism. European Journal of Endocrinology. 2014;**171**:451-460

[59] Andersen SL, Andersen S. Antithyroid drugs and birth defects. Thyroid Research. 2020;**13**:11. DOI: 10.1186/s13044-020-00085-8

[60] Kornacki J, Skrzypczak J. Fetal neck tumors - antenatal and intrapartum management. Ginekologia Polska. 2017; **88**(5):266-269

[61] Marx H, Amin P, Lazarus JH. Hyperthyroidism and pregnancy. BMJ. 2008;**336**(7645):663-667

[62] Huel C, Guibourdenche J, Vuillard E, Ouahba J, Piketty J, Oury JF, et al. Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound in Obstetrics & Gynecology. 2009;**33**:412- 420

[63] Kurtoglu S, Ozdemir. Fetal neonatal hyperthyroidism: Diagnostic and therapeutic approachment. Turkish Archives of Pediatrics. 2017;**52**(1):1-9

[64] Hudzik B, Zubelewicz-Szkodzinska B. Antithyroid drugs during

*The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes… DOI: http://dx.doi.org/10.5772/intechopen.108354*

breastfeeding. Clinical Endocrinology. 2016;**85**(6):827-830

[65] Segni M. Neonatal hyperthyroidism [updated 2019 Apr 15]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000 Available from: https://www.ncbi.nlm. nih.gov/books/NBK279019/

[66] Kurtoglu S, Ozdemir. Fetal neonatal hyperthyroidism: Diagnostic and therapeutic approachment. Turkish Archives of Pediatrics. 2017;**52**(1):1-9

[67] Törnhage CJ, Grankvist K. Acquired neonatal thyroid disease due to TSH receptor antibodies in breast milk. Journal of Pediatric Endocrinology and Metabolism. 2006;**19**(6):787-794

[68] van der Kaay DC, Wasserman JD, Palmert MR. Management of neonates born to mothers with Graves' disease. Pediatrics. 2016;**137**(4):e20151878

[69] Pyrżak B, Rumińska M, Witkowska-Sędek E, Kucharska A. Follow-up of thyroid function in children with neonatal hyperthyroidism. Frontiers in Endocrinology (Lausanne). 2022;**13**: 877119

[70] Papendieck P, Chiesa A, Prieto L, Gruñeiro-Papendieck L. Thyroid disorders of neonates born to mothers with Graves' disease. Journal of Pediatric Endocrinology & Metabolism. 2009;**22** (6):547-553

[71] Leger J. Management of fetal and neonatal Graves' disease. Hormone Research in Pædiatrics. 2017;**87**:1-6

[72] Polak M. Hyperthyroidism in early infancy: Pathogenesis, clinical features and diagnosis with a focus on neonatal hyperthyroidism. Thyroid. 1998;**8**: 1171-1177

[73] Ogilvy-Stuart AL. Neonatal thyrotoxicosis. NeoReviews. 2017;**18**(7): e422-e430

[74] Bucci I, Giuliani C, Napolitano G. Thyroid-stimulating hormone receptor antibodies in pregnancy: Clinical relevance. Frontiers in Endocrinology (Lausanne). 2017;**8**:137

[75] Neal PR, Jansen RD, Lemons JA, Mirkin LD, Schreiner RL. Unusual manifestations of neonatal hyperthyroidism. American Journal of Perinatology. 1985;**2**(03):231-235

[76] Samuels SL, Namoc SM, Bauer AJ. Neonatal thyrotoxicosis. Clinics in Perinatology. 2018;**45**(1):31-40

[77] Besancon A, Beltrand J, Le Gac I, Luton D, Polak M. Management of neonates born to women with Graves' disease: A cohort study. European Journal of Endocrinology. 2014;**170**(6): 855-862

[78] Kempers MJ, van Tijn DA, van Trotsenburg AS, de Vijlder JJ, Wiedijk BM, Vulsma T. Central congenital hypothyroidism due to gestational hyperthyroidism: Detection where prevention failed. The Journal of Clinical Endocrinology and Metabolism. 2003;**88** (12):5851-5857

[79] van Trotsenburg ASP. Management of neonates born to mothers with thyroid dysfunction, and points for attention during pregnancy. Best Practice & Research Clinical Endocrinology & Metabolism. 2020;**34**:101437

[80] Özon A, Tekin N, Şıklar Z, et al. Neonatal effects of thyroid diseases in pregnancy and approach to the infant with increased TSH: Turkish Neonatal and Pediatric Endocrinology and Diabetes Societies consensus report.

#### *Hyperthyroidism - Recent Updates*

Turkish Archives of Pediatrics. 2018;**53** (Suppl 1):S209-S223

[81] van Trotsenburg P, Stoupa A, Leger J, Rohrer T, Peters C, et al. Congenital hypothyroidism: A 2020–2021 consensus guidelines update— An ENDO-European reference network initiative endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid. 2021;**31**(3):387-419

[82] Stagnaro-Green A. Approach to the patient with postpartum thyroiditis. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**(2):334-342

[83] Argatska AB, Nonchev BI. Postpartum thyroiditis. Folia Med (Plovdiv). 2014;**56**(3):145-151

[84] Schmidt PMDS, Longoni A, Pinheiro RT, Assis AM. Postpartum depression in maternal thyroidal changes. Thyroid Research. 2022;**15**(1):6. DOI: 10.1186/ s13044-022-00124-6

[85] Lucas A, Pizarro E, Granada ML, Salinas I, Sanmarti A. Postpartum thyroid dysfunction and postpartum depression: Are they two linked disorders? Clinical Endocrinology (Oxford). 2001;**55**:809-814

[86] De Leo S, Pearce EN. Autoimmune thyroid disease during pregnancy. The Lancet Diabetes and Endocrinology. 2018;**6**(7):575-586

#### **Chapter 6**

### Thyrotoxic Hypokalemic Periodic Paralysis

*Mustafa Cesur and Irmak Sayın Alan*

#### **Abstract**

Thyrotoxic hypokalemic periodic paralysis (THPP) is a rare but life-threatening complication of hyperthyroidism characterized by recurrent episodes of muscle weakness due to intracellular potassium shifting in the presence of high levels of thyroid hormone. Attacks can be triggered by many factors. Its differential diagnosis from the other common causes of hypokalemic paralysis is necessary to maintain targeted therapy. Outcome was right away positive under potassium replacement therapy. Hyperthyroidism should be treated to prevent attacks.

**Keywords:** hypokalemia, periodic paralysis, thyrotoxicosis, pathophysiology of THPP, management of THPP

#### **1. Introduction**

Hypokalemia can be defined as a serum potassium level under 3.5 mEq/L. The symptoms of severe hypokalemia are nonspecific and mainly are related to muscular or cardiac functions and its effects on nerves. In severe and life-threatening hypokalemia (serum potassium of less than 2.5 mEq/L) generalized weakness and dangerous ventricular tachyarrhythmias may occur. Heart muscle can be affected by arrhythmias and may lead to heart failure [1, 2]. Acute decrease of serum potassium may be more arrhythmogenic than chronic hypokalemia [3].

Acute hypokalemic paralysis is a clinical syndrome presenting with low serum potassium levels and acute systemic weakness. The muscular weakness ranges from minor weakness to complete flaccid paralysis. This clinical syndrome is extremely rare. Fortunately, it is a treatable condition. Thyrotoxic hypokalemic periodic paralysis (THPP) is one of the reason of acute hypokalemic paralysis [4]. Approximately 32% of acute hypokalemic paralysis has found to be related to thyrotoxicosis [5].

The association between thyrotoxicosis and periodic paralysis was first described by Rosenfeld in 1902. THPP is a rare condition, which occurs in 2% of patients with thyrotoxicosis. THPP is mainly sporadic, but may be associated with certain HLA haplotypes [6]. There is no exact knowledge about genetic disposition of THPP. Genetic analysis identified heterozygous variants in candidate genes. But no single pathogenetic mutation has been identified. Several single-nucleotide polymorphisms in these genes have been associated with THPP. Determination of the complete

#### **Triggering factors**


#### **Table 1.**

*Triggering factors of Thyrotoxic hypokalemic paralytic episodes.*

genetic architecture in the future studies will be helpful to understand the pathophysiology of THPP [7, 8].

THPP is generally associated with intermittent episodes of muscle weakness and occasionally with severe paralysis. Paralytic attacks are mostly precipitated by strenuous exercise, high glucose intake, or hyperinsulinemia. THPP is a widespread complication of hyperthyroidism in males (85%) of Asian origin with a frequency of almost 2% [4, 9]. The case of THPP in the females is a rare occurrence. The reason for this is mysterious but proposes that androgens have a role in the pathogenesis of THPP. Cases with symptoms are generally between 20 and 40 years of age [10, 11]. Rarely it can be seen in children and adolescents [12] or elderly [13].

The best part of etiological agents for thyrotoxicosis may be related with THPP. The major agent was reported to be Graves' disease [12, 13]. Silent thyroiditis and subacute thyroiditis are the rest etiologies [4]. THPP related with Coronavirus disease 2019 (Covid-19) infection reported in some data. Higher incidence of hyperthyroidism was reported in patients with Covid-19 infection, probably related to immune response to the infection. Thyroid function was shown to be improved when the infection was resolved [14, 15].

Various circumstances, including TSH-secreting pituitary adenoma [16], using high doses of thyroxine [17, 18], and iodine-related thyrotoxicosis with inattentive use of iodine or with drugs containing iodine (e.g., iodinate contrast agents or amiodarone) [19–21] have also been involved.

One of the Turkish cases occurred as the first manifestation of interferon-alphainduced Graves' disease [22] while another occurred after radioactive iodine therapy, which led to the consideration of radiation thyroiditis [23]. There are many triggering factors [4, 24, 25]. The triggering factors of thyrotoxic hypokalemic paralytic episodes are given in **Table 1**.

#### **2. The pathophysiology of THPP**

The pathophysiology of THPP is poorly understood. In THPP, flaccid paralysis occurs with comparatively minor alterings in the serum potassium level. Hypokalemia is the characteristic evidence with elevated thyroid hormones. It is generated with a quick

#### *Thyrotoxic Hypokalemic Periodic Paralysis DOI: http://dx.doi.org/10.5772/intechopen.108283*

shift in K from the extracellular space to the intracellular department, particularly into the muscles. Increased adrenergic responses and elevated circulating levels of insulin and thyroid hormones raise Na+ /K+ -ATPase activity. Additionally, thyroid hormones rise the sensitivity of beta-receptors, so catecholamine-mediated cellular K uptake is raised [26, 27]. These suggestions may explain why insulin and epinephrine stimulate paralytic attacks. Carbohydrate-rich meals increase insulin release, and stress-related factors (e.g., emotional stress, cold, trauma, and infection) increase epinephrine delivery. Exercise also delivers K from the skeletal muscles, while rest encourages flow of K, so paralytic attacks may be seen during rest after strenuous exercise [28].

The robust preference for THPP to occur in males brings forward that androgens may take part to pathogenesis of THPP. Androgens have been reported to enhance the expression and activity of the Na+ /K+ -ATPase and hence related with TPP attacks [29]. Potassium channel Kir2.6 gene mutations have been established to take a role in THPP. Kir2.6 is mainly expressed in skeletal muscle and is transcriptionally arranged by thyroid hormone. Mutation of the gene coding this channel has been established in THPP cases and is related with high prevalence of paralytic attacks in those patients [30].

#### **3. Differential diagnosis**

In an acute attack, THPP must be distinguished from other causes of acute hypokalemic paralysis. Hypokalemic paralysis symbolizes a heterogeneous category of disorders, which cause an ultimate mutual pathway existing as acute weakness and hypokalemia. Hypokalemic paralysis can be divided into two main groups. The first group contains the patients with hypokalemic periodic paralysis, which is related to

*Pathogenesis of hypokalaemic paralysis in transcellular distribution of potassium without depletion.*


**Table 2.**

*Differential diagnosis of hypokalemic paralysis.*

an acute exchange of potassium into the cells (**Figure 1**). The second group contains the patients presenting with hypokalemic paralysis, which is related to potassium depletion. Diagnosis among paralytic attacks is hard as the patient may have normal force and potassium levels. Electromyography shows unusualness in a few patients but is frequently normal, particularly among episodes when no clinically detectable weakness is present. Hypokalemic paralysis happens in different situations, and the diagnosis may require a broad research for the underlying etiology since the treatment changes according to the reason [31].

The diagnosis of THPP is made based on clinical presentation and exclusion of disorders associated with low potassium (**Table 2**).

#### **4. Clinical features**

THPP attacks mostly occur in the late night or early morning and last from a few hours up to several days. Prodromal symptoms such as aches, cramps, and stiffness can be seen [32]. Generally, the proximal muscles are more seriously affected than the distal muscles. The acute episode at first involves the lower limbs, followed by girdle muscles and thereafter upper limb. Atypical findings such as asymmetric paralysis are uncommon. Presentations alter widely from mild, transient, self-limited motor dysfunction to total flaccid paralysis, with recovery occurring first in those muscles affected last. Bladder, bowel, and sensory functions are generally not affected and mental skills are never damaged [10]. Paralysis of respiratory, bulbar, and ocular muscles has been rarely reported in severe attacks of THPP. Respiratory muscle involvement, even though rare, generally can be fatal [33]. Deep tendon reflexes are prominently reduced or absent. Moriyama et al. reported that sudden deafness in a man with THPP, circulatory failure, and electrolyte instability in the right inner ear was accepted to have caused the deafness [34]. Patients completely recover between the attacks [26].

#### **5. Laboratory features**

Hypokalemia is the main laboratory finding in THPP. However, normokalemic THPP cases have also been reported [35, 36]. Normokalemia may lead to overlooked diagnosis [36]. The level of hypokalemia is important [31]. Serum potassium level

#### *Thyrotoxic Hypokalemic Periodic Paralysis DOI: http://dx.doi.org/10.5772/intechopen.108283*

may be one of the markers of survey of the disease for its reasoning of fatal and life-threatening ventricular arrhythmias [37, 38]. Hypomagnesemia and hypophosphatemia have been reported to be common in THPP. These laboratory results may aid differentiate THPP from familial hypokalemic periodic paralysis [39]. Elevated serum T3 and T4, low serum TSH levels, and thyroid uptake scan showing symmetric diffuse uptake are component of the diagnostic assessment. Patients with elevated T3 and normal T4 levels have been reported, particularly in patients who have Graves' disease or an adenoma who usually have T3 thyrotoxicosis [40]. Serum creatine phosphokinase (CPK) was found to be high [39, 41]. Rhabdomyolysis may be seen in severe THPP [42]. In addition to hypokalemia [43] and hypophosphataemia [44], hyperthyroidism alone may cause rhabdomyolysis [45]. ECG alterations in THPP vary from nondiagnostic to those demonstrating typical features of hypokalemia [46]. ECG alterations related with hypokalemia and/or other ECG abnormalities may be seen. ECG findings may help in early diagnosis of THPP [47, 48]. Sinus tachycardia, ventricular tachycardia, ventricular fibrillation, high QRS voltage, first-degree AV block, atrial flutter, and atrial fibrillation are significant signs proposing THPP in patients who present with paralysis and hypokalemia [48–50]. An artificial-intelligence-assisted-ECG system trustworthy recognizes hypokalemia in patients with paralysis, and combining with routine blood tests makes precious judgment assistance for the early diagnosis of THPP [51].

#### **6. Management**

Patients with acute paralysis must be hospitalized in a monitored condition for cardiac arrhythmias. Acute management of THPP contains potassium chloride replacement, cautious observation, and close monitoring of serum potassium levels. Potassium replacement can be done in two ways: oral or intravenous. A recommended protocol is 30 mEq of oral potassium every 2 hours until recovery begins, with a maximum dose of 90 mEq in 24 hours. Intravenous supplementation is the major choice if the patient shows signs of cardiac dysrhythmia, respiratory distress or is unable to take oral medications. The dosage of potassium varies between patients and can be standardized according to renal clearance and cardiovascular condition. Potassium replacement should not exceed 90 mEq/24 h because of the possibility of rebound hyperkalemia. Rebound hyperkalemia appears to be an important trouble in THPP, taking place in approximately 40–59% of treated attacks [4, 10, 52, 53]. In contrast to familial periodic paralysis, regular oral potassium supplementation is ineffective for prevention of the attacks in THPP [53]. Imminent monitoring of serum potassium levels throughout the acute attack is necessary. Continual cardiac monitoring is suggested for all patients throughout medical management and observation. A cardiology consultation should be provided for serious arrhythmias/ECG changes. Correction of hypomagnesemia, if present, is additionally suggested.

The best way to prevent and to permanently treat the periodic paralysis is to treat the thyrotoxicosis permanently. THPP does not disappear completely unless patients become euthyroid. Thus, the management of hyperthyroidism is the mainstay of therapy. Permanent treatment is so important and could be done by antithyroid drugs, radioiodine therapy, or surgery [27]. During treatment of hyperthyroidism, precipitating factors should be avoided. While antithyroid drugs may be used to induce remission, the performance of this therapy is changeable and relapses are frequent. By the end of the acute attack, radioiodine therapy or thyroid surgery is preferable to

permanently end the thyrotoxicosis. For high recurrence rates of long-term treatment with antithyroid drugs, early permanent therapy, especially with radioactive iodine, is recommended because surgical stress may further induce paralysis. However, surgical therapy with close monitoring can be performed if necessary [4]. Chemical ablation has mainly shown benefit in elderly individuals, pregnant, cardiac and pediatric patients [54]. Non-selective beta-blockers (e.g., propranolol) have been shown to significantly improve thyrotoxic symptoms and maintain relief of paralytic attacks by blocking catecholamines' effect on ion channels [55]. Selective β-blockers do not act on skeletal muscle, which makes them less beneficial in the treatment of THPP [27]. In spite of likely benefits, beta-blockers (principally non-selective agents) are known to have a mild deleterious effect other metabolic parameters [56].

The effects of glucocorticoids in the management of hyperthyroidism have been evaluated in many different studies. Even though glucocorticoids have been used to treat hyperthyroidism, they may further cause harmful effects, including the development of THPP.

Glucocorticoids may induce hypokalemia by increasing the Na<sup>+</sup> /K+ -ATPase level in skeletal muscle and also by creating hyperinsulinemia. In addition, glucocorticoids can also release muscle weakness by stimulating myopathy and renal potassium waste owing to its mineralocorticoid effects [11]. Consequently, glucocorticoids can trigger these attacks. This is an infrequent complication of thyrotoxicosis. But for physicians, it is important to be aware of the risk of provoking thyrotoxic paralysis when using high-dose glucocorticoids in the thyrotoxic phase [57]. Lastly, acetazolamide may worsen the attacks in THPP and should be avoided [52].

In conclusion, THPP is rare but life-threatening complication of thyrotoxicosis. It needs early diagnosis and immediate treatment of hypokalemia, then permanent therapy of thyrotoxicosis.

#### **Author details**

Mustafa Cesur1 \* and Irmak Sayın Alan<sup>2</sup>

1 Endocrinology and Metabolic Disease Department, Ankara Guven Hospital, Ankara, Türkiye

2 Internal Medicine Department, Ankara Guven Hospital, Ankara, Türkiye

\*Address all correspondence to: drcesur@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Kardalas E, Paschou SA, Anagnostis P, Muscogiuri G, Siasos G, Vryonidou A. Hypokalemia: a clinical update. Endocrine Connections. 2018;**7**(4):R135-R146. DOI: 10.1530/EC-18-0109

[2] Skogestad J, Aronsen JM. Hypokalemia-induced arrhythmias and heart failure: New ınsights and ımplications for therapy. Frontiers in Physiology. 2018;**9**:1500. DOI: 10.3389/ fphys.2018.01500

[3] Shapiro JI, Banerjee A, Reiss OK, Elkins N. Acute and chronic hypokalemia sensitize the isolated heart to hypoxic injury. The American Journal of Physiology. 1998;**274**(5):H1598-H1604. DOI: 10.1152/ajpheart.1998.274.5.H1598

[4] Cesur M, Bayram F, Temel MA, Ozkaya M, Kocer A, Ertorer ME, et al. Thyrotoxic hypokalaemic periodic paralysis in a Turkish population: Three new case reports and analysis of the case series. Clinical Endocrinology. 2008;**68**(1):143-152. DOI: 10.1111/j.1365-2265.2007.03014.x

[5] Veltri KT, Mason C. Medicationinduced hypokalemia. Pharmacy and Therapeutics. 2015;**40**(3):185-190

[6] Tamai H, Tanaka K, Komaki G, Matsubayashi S, Hirota Y, Mori K, et al. HLA and thyrotoxic periodic paralysis in Japanese patients. The Journal of Clinical Endocrinology and Metabolism. 1987;**64**(5):1075-1078. DOI: 10.1210/ jcem-64-5-1075

[7] Rasheed E, Seheult J, Gibney J, Boran G. Does thyrotoxic periodic paralysis have a genetic predisposition? A case report. Annals of Clinical Biochemistry. 2018;**55**(6):713-716. DOI: 10.1177/0004563218785395

[8] Zhao SX, Liu W, Liang J, Gao GQ, Zhang XM, Yao Y, et al. China consortium for the genetics of autoimmune thyroid disease. Assessment of molecular subtypes in Thyrotoxic periodic paralysis and graves disease among Chinese Han adults: A population-based genomewide association study. JAMA Network Open. 2019;**2**(5):e193348. DOI: 10.1001/ jamanetworkopen.2019.3348

[9] Ahlawat SK, Sachdev A. Hypokalaemic paralysis. Postgraduate Medical Journal. 1999;**75**(882):193-197. DOI: 10.1136/pgmj.75.882.193

[10] Tinker TD, Vannatta JB. Thyrotoxic hypokalemic periodic paralysis: Report of four cases and review of the literature (1). The Journal of the Oklahoma State Medical Association. 1987;**80**(1):11-15

[11] El-Hennawy AS, Nesa M, Mahmood AK. Thyrotoxic hypokalemic periodic paralysis triggered by high carbohydrate diet. American Journal of Therapeutics. 2007;**14**(5):499-501. DOI: 10.1097/MJT.0b013e31814daf53

[12] Roh JG, Park KJ, Lee HS, Hwang JS. Thyrotoxic hypokalemic periodic paralysis due to Graves' disease in 2 adolescents. Annals of Pediatric Endocrinology & Metabolism. 2019;**24**(2):133-136. DOI: 10.6065/ apem.2019.24.2.133

[13] Bilha S, Mitu O, Teodoriu L, Haba C, Preda C. Thyrotoxic periodic paralysis-a misleading challenge in the emergency department. Diagnostics (Basel). 2020;**10**(5):316. DOI: 10.3390/ diagnostics10050316

[14] Khoo B, Tan T, Clarke SA, Mills EG, Patel B, Modi M, et al. Thyroid function before, during, and after COVID-19. The Journal of Clinical Endocrinology and Metabolism. 2021;**106**(2):e803-e811. DOI: 10.1210/clinem/dgaa830

[15] Fitriani F, Susanti VY, Ikhsan MR. COVID-19 infectionrelated Thyrotoxic hypokalemic periodic paralysis. Case Reports in Endocrinology. 2022;**2022**:1382270. DOI: 10.1155/2022/1382270

[16] Alings AM, Fliers E, de Herder WW, Hofland LJ, Sluiter HE, Links TP, et al. A thyrotropin-secreting pituitary adenoma as a cause of thyrotoxic periodic paralysis. Journal of Endocrinological Investigation. 1998;**21**(10):703-706. DOI: 10.1007/BF03350802

[17] Chen YC, Fang JT, Chang CT, Chou HH. Thyrotoxic periodic paralysis in a patient abusing thyroxine for weight reduction. Renal Failure. 2001;**23**(1):139- 142. DOI: 10.1081/jdi-100001294

[18] Patel AJ, Tejera S, Klek SP, Rothberger GD. Thyrotoxic peiıodic paralysis in a competitive bodybuilder with thyrotoxicosis factitia. AACE Clinical Case Reports. 2020;**6**(5):e252-e256. DOI: 10.4158/ ACCR-2020-0154

[19] Tran HA. Inadvertent iodine excess causing thyrotoxic hypokalemic periodic paralysis. Archives of Internal Medicine. 2005;**165**(21):2536. DOI: 10.1001/ archinte.165.21.2536-a

[20] Kane MP, Busch RS. Drug-induced thyrotoxic periodic paralysis. The Annals of Pharmacotherapy. 2006;**40**(4): 778-781. DOI: 10.1345/aph.1G543

[21] Laroia ST, Zaw KM, Ganti AK, Newman W, Akinwande AO. Amiodarone-induced thyrotoxicosis presenting as hypokalemic periodic paralysis. Southern Medical Journal. 2002;**95**(11):1326-1328

[22] Cesur M, Gursoy A, Avcioglu U, Erdogan MF, Corapcioglu D, Kamel N. Thyrotoxic hypokalemic periodic paralysis as the first manifestation of interferonalpha-induced graves disease. Journal of Clinical Gastroenterology. 2006;**40**(9):864-865. DOI: 10.1097/01. mcg.0000212660.59021.a3

[23] Akar S, Comlekci A, Birlik M, Onen F, Sari I, Gurler O, et al. Thyrotoxic periodic paralysis in a Turkish male; the recurrence of the attack after radioiodine treatment. Endocrine Journal. 2005;**52**(1):149-151. DOI: 10.1507/ endocrj.52.149

[24] Lin SH. Thyrotoxic periodic paralysis. Mayo Clinic Proceedings. 2005;**80**(1):99-105. DOI: 10.1016/ S0025-6196(11)62965-0

[25] Mellgren G, Bleskestad IH, Aanderud S, Bindoff L. Thyrotoxicosis and paraparesis in a young woman: Case report and review of the literature. Thyroid. 2002;**12**(1):77-80. DOI: 10.1089/105072502753452002

[26] Cesur M, Ilgin SD, Baskal N, Gullu S. Hypokalemic paralysis is not just a hypokalemic paralysis. European Journal of Emergency Medicine. 2008;**15**(3):150-153. DOI: 10.1097/ MEJ.0b013e3282bf6ee3

[27] Kung AW. Clinical review: Thyrotoxic periodic paralysis: A diagnostic challenge. The Journal of Clinical Endocrinology and Metabolism. 2006;**91**(7):2490-2495. DOI: 10.1210/jc.2006-0356

[28] Ober KP. Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine (Baltimore). 1992;**71**(3):109-120. DOI: 10.1097/00005792-199205000-00001

[29] Biering H, Bauditz J, Pirlich M, et al. Manifestation of thyrotoxic periodic

*Thyrotoxic Hypokalemic Periodic Paralysis DOI: http://dx.doi.org/10.5772/intechopen.108283*

paralysis in two patients with adrenal adenomas and hyperandrogenaemia. Hormone Research. 2003;**59**(6):301-304

[30] Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 2010;**140**(1):88-98. DOI: 10.1016/j. cell.2009.12.024

[31] Stedwell RE, Allen KM, Binder LS. Hypokalemic paralyses: A review of the etiologies, pathophysiology, presentation, and therapy. The American Journal of Emergency Medicine. 1992;**10**(2):143- 148. DOI: 10.1016/0735-6757(92)90048-3

[32] Sanyal D, Bhattacharjee S. Thyrotoxic hypokalemic periodic paralysis as the presenting symptom of silent thyroiditis. Annals of Indian Academy of Neurology. 2013;**16**(2):218-220. DOI: 10.4103/0972-2327.112471

[33] Liu YC, Tsai WS, Chau T, Lin SH. Acute hypercapnic respiratory failure due to thyrotoxic periodic paralysis. The American Journal of the Medical Sciences. 2004;**327**(5):264-267. DOI: 10.1097/00000441-200405000-00025

[34] Moriyama K, Nozaki M, Kudo J, Takita A, Tatewaki E, Yasuda K. Sudden deafness in a man with thyrotoxic hypokalemic periodic paralysis. Japanese Journal of Medicine. 1988;**27**(3):329-332. DOI: 10.2169/ internalmedicine1962.27.329

[35] González-Treviño O, Rosas-Guzmán J. Normokalemic thyrotoxic periodic paralysis: A new therapeutic strategy. Thyroid. 1999;**9**(1):61-63. DOI: 10.1089/ thy.1999.9.61

[36] Wu CC, Chau T, Chang CJ, Lin SH. An unrecognized cause of paralysis in

ED: Thyrotoxic normokalemic periodic paralysis. The American Journal of Emergency Medicine. 2003;**21**(1):71-73. DOI: 10.1053/ajem.2003.50005

[37] Randall BB. Fatal hypokalemic thyrotoxic periodic paralysis presenting as the sudden, unexplained death of a Cambodian refugee. The American Journal of Forensic Medicine and Pathology. 1992;**13**(3):204-206. DOI: 10.1097/00000433-199209000- 00006

[38] Loh KC, Pinheiro L, Ng KS. Thyrotoxic periodic paralysis complicated by nearfatal ventricular arrhythmias. Singapore Medical Journal. 2005;**46**(2):88-88

[39] Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. Archives of Internal Medicine. 1999;**159**(6):601-606. DOI: 10.1001/ archinte.159.6.601

[40] Griggs RC, Bender AN, Tawil R. A puzzling case of periodic paralysis. Muscle & Nerve. 1996;**19**(3):362-364. DOI: 10.1002/(SICI)1097-4598 (199603)19:3<362::AID-MUS13>3. 0.CO;2-U

[41] Sabau I, Canonica A. Hypokalaemic periodic paralysis associated with controlled thyrotoxicosis. Schweizerische Medizinische Wochenschrift. 2000;**130**(44):1689-1691

[42] Kilpatrick RE, Seiler-Smith S, Levine SN. Thyrotoxic hypokalemic periodic paralysis: Report of four cases in black American males. Thyroid. 1994;**4**(4):441-445. DOI: 10.1089/ thy.1994.4.441

[43] Singhal PC, Abramovici M, Venkatesan J, Mattana J. Hypokalemia and rhabdomyolysis. Mineral and Electrolyte Metabolism. 1991;**17**(5):335-339

[44] Amanzadeh J, Reilly RF Jr. Hypophosphatemia: An evidence-based approach to its clinical consequences and management. Nature Clinical Practice. Nephrology. 2006;**2**(3):136-148. DOI: 10.1038/ncpneph0124

[45] Lichtstein DM, Arteaga RB. Rhabdomyolysis associated with hyperthyroidism. The American Journal of the Medical Sciences. 2006;**332**(2):103-105. DOI: 10.1097/00000441-200608000- 00012

[46] Ee B, Cheah JS. Electrocardiographic changes in thyrotoxic periodic paralysis. Journal of Electrocardiology. 1979;**12**(3):263-279. DOI: 10.1016/ s0022-0736(79)80059-x

[47] Ngo A, Lim SH, Charles RA, Goh SH. Electrocardiographical case. Young man with generalised myalgia. Singapore Medical Journal. 2005;**46**(1):38-40

[48] Hsu YJ, Lin YF, Chau T, Liou JT, Kuo SW, Lin SH. Electrocardiographic manifestations in patients with thyrotoxic periodic paralysis. The American Journal of the Medical Sciences. 2003;**326**(3):128-132. DOI: 10.1097/00000441-200309000- 00004

[49] Tsai IH, Su YJ. Thyrotoxic periodic paralysis with ventricular tachycardia. Journal of Electrocardiology. 2019;**54**:93-95. DOI: 10.1016/j. jelectrocard.2019.04.001 Epub 2019 Apr 4

[50] Sanchez-Nadales A, Celis-Barreto V, Diaz-Sierra A, Sanchez-Nadales A, Lewis A, Sleiman J. When cardiology meets endocrinology: Sustained atrial flutter associated with thyrotoxic periodic paralysis. Oxford Medical

Case Reports. 2022;**2022**(3):omac020. DOI: 10.1093/omcr/omac020

[51] Lin C, Lin CS, Lee DJ, Lee CC, Chen SJ, Tsai SH, et al. Artificial intelligenceassisted electrocardiography for early diagnosis of Thyrotoxic periodic paralysis. Journal of the Endocrine Society. 2021;**5**(9):bvab120. DOI: 10.1210/jendso/ bvab120

[52] Lu KC, Hsu YJ, Chiu JS, Hsu YD, Lin SH. Effects of potassium supplementation on the recovery of thyrotoxic periodic paralysis. The American Journal of Emergency Medicine. 2004;**22**(7):544-547. DOI: 10.1016/j.ajem.2004.09.016

[53] Cope TE, Samaraweera AP, Burn DJ. Thyrotoxic periodic paralysis: Correct hypokalemia with caution. The Journal of Emergency Medicine. 2013;**45**(3):338-340. DOI: 10.1016/j. jemermed.2012.11.107

[54] Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocrine Practice. 2002;**8**(6):457-469. DOI: 10.4158/1934-2403-8.6.457

[55] Shayne P, Hart A. Thyrotoxic periodic paralysis terminated with intravenous propranolol. Annals of Emergency Medicine. 1994;**24**(4):736-740. DOI: 10.1016/ s0196-0644(94)70286-1

[56] Cooper-DeHoff RM, Pacanowski MA, Pepine CJ. Cardiovascular therapies and associated glucose homeostasis: Implications across the dysglycemia continuum. Journal of the American College of Cardiology. 2009;**53**(5

*Thyrotoxic Hypokalemic Periodic Paralysis DOI: http://dx.doi.org/10.5772/intechopen.108283*

Suppl):S28-S34. DOI: 10.1016/j. jacc.2008.10.037

[57] Tigas S, Papachilleos P, Ligkros N, Andrikoula M, Tsatsoulis A. Hypokalemic paralysis following administration of intravenous methylprednisolone in a patient with Graves' thyrotoxicosis and ophthalmopathy. Hormones (Athens, Greece). 2011;**10**(4):313-316. DOI: 10.14310/horm.2002.1323

### **Chapter 7**

## Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism

*Hari Krishnan Krishnamurthy, Swarnkumar Reddy, Vasanth Jayaraman, Karthik Krishna, Karenah E. Rajasekaran, Tianhao Wang, Kang Bei and John J. Rajasekaran*

#### **Abstract**

Thyroid hormones play a pivotal role in the overall physiological and developmental function of the human body. Alterations in thyroid hormones drastically affect regular metabolic processes as well as physical well-being. Thyroid alterations directly influence the functioning of all major body systems including cardiovascular, neurological, gastrointestinal, etc. The thyroid hormonal imbalance is primarily classified into two major conditions: hyperthyroidism and hypothyroidism. The present chapter details the pathology of thyroid imbalance in the context of human reproductive health, autoimmunity, and micronutrient imbalance. Some novel micronutrient associations independent of iodine deficiencies are discussed. Additionally, the early predictive capability of the anti-TPO antibody as well as other autoimmune correlations are discussed. Given its role in reproductive health, the associations of various sex hormones with thyroid function were also explored.

**Keywords:** hyperthyroidism, micronutrients, Graves' disease, iodine, hormones, antibodies

#### **1. Introduction**

Thyroid disorders are the most common type of endocrine dysfunction worldwide, with an estimated prevalence of 5–6% in the US population. Thyroid disorders can be highly differentiated from other endocrine diseases in terms of diagnosis, accessibility of treatment methods, etc. [1]. Early diagnosis and treatment of thyroid diseases remain a cornerstone of management. It's well known that thyroid hormones play crucial roles in regulating various metabolic processes. Thyroid hormone synthesis is a sensitive and feedback loop-dependent system controlled by the hypothalamus-pituitary-thyroid (HPT) axis. The regular functioning of the thyroid gland is a delicate balance among the hypothalamus, pituitary gland, and the thyroid gland [2]. The feedback loop slows down the production of thyrotropin-releasing hormone (TRH) in the hypothalamus which in turn slows

down the production of thyroid-stimulating hormone and down-regulates thyroid hormone when excess is synthesized [3], the reverse happens when the thyroid hormones are low. Any biochemical alterations in this feedback loop results in under-function or over-function of the thyroid gland resulting in catastrophic health consequences [4, 5]. Thyroid disease results from a broad spectrum of pathologies including autoimmune disorders, infectious diseases, organ damage, pharmaceutical compounds, nutritional deficiencies, and environmental factors.

Deficiency of nutrients, in particular micronutrients, results in various nonspecific physiological effects including metabolic disorders, suppressed immune responses, and altered endocrine functioning—including that of the thyroid gland. Micronutrients play a key role in enzyme synthesis, immune function, and regulating cellular homeostasis [6, 7]. Optimum levels of iodine intake have long been associated with thyroid health, it is, however, important to consider the optimal supply of other micronutrients that aid in thyroid function as well.

Recent studies have demonstrated the early diagnosis of autoimmune thyroid diseases could reduce the severity of the consequent thyroid disease and reduce its effect on the resulting comorbid conditions. Autoimmune thyroid disease is the most common thyroid disorder affecting the reproductive system in both males and females resulting in infertility. The current chapter details the most important causes of thyroid dysfunction and also discusses recent advances in thyroid research covering various aspects. The application of anti-TPO as an early predictor of various thyroid disorders and the effect of thyroid alteration on human reproductive health is also discussed [8, 9].

#### **2. The pathology of hyperthyroidism**

Hyperthyroidism is characterized by exceedingly high secretions of free thyroxine (T4), triiodothyronine, or both. The elevated levels of thyroid hormone in tissues result in systemic clinical manifestations such as weight loss, palpitations, and heat intolerance that result in thyrotoxicosis [10]. Graves' disease, toxic multinodular goiters, and toxic adenomas are the most common causes of hyperthyroidism resulting from mutations in genes that regulate the TSH receptor causing familial or nonautoimmune hyperthyroidism (FNAH) [11]. In FNAH the disease-causing mutations are inherited in an autosomal dominant manner and distinguished by a positive history of inherited non-autoimmune hyperthyroidism exhibiting variable onset symptoms. With FNAH, patients are clinically presented with goiter with no signs of autoimmune responses. Iodine-induced hyperthyroidism is one of the major nutritional causes of hyperthyroidism. Others include germ cell tumors, thyroid cancer, trophoblastic, struma ovarii, TSH-producing pituitary tumors, and medications such as lithium or pregnancy. Hyperthyroidism resulting from these reasons is generally self-limited for a period of time and does not require any medications [12, 13].

#### **3. Etiology and epidemiology**

Hyperthyroidism is a clinical state resulting from the disproportionate secretion of thyroid hormones. The most common causes include Graves' disease and toxic nodular goiter and other less common causes include factitious thyroiditis, iodineinduced hyperthyroidism, subacute thyroiditis, and postpartum thyroiditis [14]. Graves' disease is the most common cause of hyperthyroidism in the United States

#### *Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.109375*

and other western countries. The etiology of Graves' disease remains multifactorial, as it arises by the loss of immunotolerance resulting in the development of autoimmune responses this induces the thyroid follicular cells by binding to TSH receptors, Graves' disease is the most common cause of hyperthyroidism in the young population. Deficiency of vitamin D and selenium, thyroid damage, immunomodulating drugs, beta-blockers, and infections also account for the development of Graves' disease [15]. Toxic multinodular goiter was found to be the most common cause of hyperthyroidism in the older population [16]. The use of excessive pharmaceutical thyroid hormones or inappropriate intake of external hormones results in factitious thyroiditis. Due to a well-received side effect of weight loss, thyroxine has the potential for abuse, and any history of a hyperthyroid patient should include a medication list and an assessment of possible misuse (whether intentional or unintentional). Struma ovarii, metastatic follicular thyroid cancer, and TSH-secreting pituitary adenoma are the other less common causes of hyperthyroidism [16].

The global epidemiology of hyperthyroidism can be defined in correspondence to the population in iodine-deficient regions and iodine-sufficient regions. In Europe, the dietary intake of iodine is the major cause of hyperthyroidism, whereas in a few cases autoimmune disease results in hyperthyroidism. In the US, Grave's disease is the most common factor of hypothyroidism in the younger population, whereas toxic nodular goiter is more common among the older. The overall prevalence of hyperthyroidism is 0.8% and 1.3% in Europe and the USA respectively. The prevalence of overt hyperthyroidism rates 0.1 per 1000 men and 0.4 per 1000 women in Europe, whereas overt hyperthyroidism accounts for 0.5% of the total US population.

#### **4. Forms of thyroid diseases**

#### **4.1 Graves' disease**

Graves' disease is seen as the prime cause of hyperthyroidism and accounts for more than 70% of all hyperthyroid cases. Annually over 2% of women and 0.2% of men were reported with Graves' disease globally [17]. Graves' disease was found to be much more frequent in females, particularly during childhood, and more prevalent during puberty. The pathology of Graves' disease remains unclear, the genetic predisposition of the disease in concordance with additional environmental factors can be given as the most common cause of Graves' disease [18, 19]. The infiltration of the thyroid gland by autoreactive T and B cells synthesis of cytokines results in producing TSH-receptor Ab. The production of auto-antibodies and the preexistence of genetic predisposition of Graves' along with external factors including a recurring infection, stress, smoking, or oral iodine results in Graves' mediated hyperthyroidism. The most common first-line therapy includes antithyroid drugs (ATD) [20, 21]. The lower liver toxicity makes thiamazole as most preferred ATD. The suboptimal remission rate limits the use of thiamazole therapy and offers the use of radioiodine therapy as primary treatment. Carbimazole and its active metabolite such as propylthiouracil (PTU) and methimazole (MMI) are other commonly used ATD for Graves'.

#### **4.2 Thyroiditis (Hashimoto's disease)**

Hashimoto thyroiditis is presented as an autoimmune disease that results from the self-destruction of thyroid cells by auto-antibody-mediated immune responses [22].

Progressive fibrosis resulting from damaged thyroid tissue by antithyroid antibodies is the most common pathology of Hashimoto's disease. Based on the pathology Hashimoto's can also be termed as chronic lymphocytic thyroiditis or autoimmune thyroiditis. Hashimoto's disease is most prevalent among women than men, particularly among women aged between 30 and 50 years [23]. Diagnosis remains a constraint in Hashimoto's as it still takes time even after the disease progression. Monitoring elevated levels of antithyroid peroxidase along with depleted levels of free thyroxine and elevated TSH is the most common diagnostic method [24]. Levothyroxine is the most common medication which acts by converting T4 to T3, the active form of thyroid hormone [25].

#### **4.3 Thyrotoxicosis**

The physiological malfunctions in the expression of excessive levels of thyroid hormones are characterized as thyrotoxicosis. Thyrotoxicosis refers to the release of excess thyroid hormone resulting from the rapid distraction of thyroid tissue and it is not associated with hyperfunction of the thyroid gland [26]. Viral infection or autoimmune malfunctions resulting in the inflammation of the thyroid gland is the prime cause of thyrotoxicosis [27]. High levels of circulating thyroid hormones exhibit a direct inotropic effect by increasing α- to β-myosin heavy chain expression which affects cardiac contraction. Increased appetite, heat intolerance, and increased basal metabolic rate results in metabolism and increased food intake [28, 29]. Based on the degree of the increased rate of metabolism, nutritional deficiency and chronic caloric inadequacy ensue. The increased basal metabolic rate results in increased synthesis and degradation of the protein. Increased protein metabolism results in severe thyrotoxicosis and a radical decrease in net protein content can be evidenced by muscle wasting, proximal muscle weakness, and loss of weight [30].

#### **4.4 Toxic nodular goiter**

Toxic nodular goiter is a hormonally heterogeneous disorder, goiter is a multinodular hyperthyroidism characterized by multifunctional thyroid nodules with normal, increased, or decreased thyroid hormone production [31]. The functional heterogenicity of normal follicular cells through genetic factors and also through accruing new inheritable qualities by replicating thyroid cells are the two major primary factors of nodular goiter [32]. Secondary factors include external aspects such as smoking, stress, high levels of TSH, pharmaceutical agents, TSF (IGF-1), and other exogenous factors. Iodine plays a pivotal role development of nodular goiters. Iodine deficiency results in hyperplasia with increased TSH levels, with raise in iodine to a normal level hyperplasia, go into the resting phase [33]. These physiological alterations result in the development of diffuse hyperplasia with a higher risk of developing uni-nodule or multi-nodular goiter. Toxic multinodular goiter exhibits characteristic precursors such as single toxic adenomas or nontoxic multinodular goiter. The other complications include congestive heart failure, rapid heart rate, and atrial fibrillation, which might also result in osteoporosis [34].

#### **5. Causes of hyperthyroidism**

Hyperthyroidism is a multifactorial hormonal disorder that varies according to the patient's age, degree of hormone synthesis, the incidence of similar health conditions, and extent of the illness. The clinical presentation of hyperthyroidism

#### *Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.109375*

differentiates with each of the conditions given above [35]. Grave's disease and thyroiditis are the most common causes of hyperthyroidism. Grave's is commonly characterized as an autoimmune disease with an overproduction of thyroid hormone and this can be inherited or mostly associated with other autoimmune diseases. Thyroiditis is also an autoimmune condition resulting from inflammation of the thyroid gland [36]. An onset of thyrotoxic symptoms results from a hormone leak from the inflamed gland in subacute thyroiditis. Lymphocytic thyroiditis results from transient inflammatory causes and is difficult to distinguish from Graves at the early acute stage.

Various other factors influence the cause of hyperthyroidism which includes, but not limited to, such as excess thyroid hormone supplementation, iodine-induced hyperthyroidism, noncancerous tumor of the pituitary gland, and drugs associated with hyperthyroidism.

#### **5.1 Exogenous thyroid hormone (acute or chronic)**

The excessive intake of liothyronine, levothyroxine, or desiccated thyroid either intentionally or inadvertent may result in exogenous hyperthyroidism. Prevalence of exogenous hyperthyroidism is more common in elderly people than endogenous hyperthyroidism due to an intentional overdose of thyroid hormone [37]. Levothyroxine is the most common suppressive dose of thyroxine administered to treat patients with goiter and to suppress tumor growth. Drugs used for treating depression, infertility, and obesity were also known to cause exogenous hyperthyroidism. Overdose of thyroid hormones may result in bone loss, cardiac dysfunction, and myocardial infarction. Exogenous hyperthyroidism typically exhibits symptoms of thyrotoxicosis [38, 39].

#### **5.2 Iodine-induced hyperthyroidism**

Iodine-induced hyperthyroidism was first stated in 1821 and has been recurrently observed in patients when introduced to iodine in iodine-deficient areas. It was also observed in patients without a history of thyroid disease in iodine-sufficient areas. The disorder has been reported later in relatively low iodine intakes regions such as western Europe and regions with iodine-deficient goiter. Iodineinduced hyperthyroidism has been reported in iodine-sufficient areas such as the United States where iodine intake was far above the minimum daily requirement (50 to 100µg). The syndrome was commonly reported in iodine-sufficient areas without any other sign of thyroid diseases. This might result from pharmacological doses of iodine from common drugs such as Betadine, Iodo-Niacin, amiodarone, and various other radiographic dyes. Globally 800 million people are at risk of iodine deficiency (ID) and related disorders. Iodine supplementation is the most preventable approach to eliminating the risk of ID disorders. The term iodide refers to the biological form of the free element (inorganic), while iodine includes both inorganic iodides (I-) and iodine covalently bound to tyrosine [40]. The thyroid adopts several mechanisms to compensate for the iodine deficiency and to maintain sufficient thyroid production. Prolonged compensatory mechanisms result in the development of multifunctional autonomous growth and function of the thyroid with induced mutation of TSH receptors by harboring scattered cell clones [12, 41]. A high prevalence of multinodular goiter and nodular hyperthyroidism may be associated with mild prolonged ID (**Figure 1**) [42].

**Figure 1.** *Metabolic pathway of thyroid iodination and deiodination mediated by iodine deiodinases.*

#### **5.3 Noncancerous tumors of the pituitary gland**

Thyrotroph adenomas are pituitary tumors that induce overproduction of thyroidstimulating hormone resulting in hyperthyroidism. Among pituitary adenomas, thyrotropic adenomas account for less than 1% and are a rare cause of hyperthyroidism [43]. Pituitary adenomas are mostly benign and localized in the pituitary gland. Tumors spread to nearby tissues by expansion or invasion of their surroundings or tissue displacement and usually do not spread to other body parts [31]. TSH- secreting adenomas widely produce TSH (72%) alone where in certain cases, elevated secretion

*Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.109375*

of TSH by adenomas results in activating various other hormones such as gonadotrophins, prolactinoma, and growth hormone which results in various physiological functioning of the brain by affecting cavernous sinus. Most of the thyroid-adenomas are macroadenomas (<10 mm) [44]. Hyperthyroidism along with thyrotroph adenomas are frequently associated with loss of vision, headache, visual defects, and loss of anterior pituitary functioning. Atrial fibrillation, thyrotoxic failure, and vertebral fracture are the few deleterious effects of thyrotroph adenomas [45].

#### **5.4 Drug-associated hyperthyroidism**

Drug-associated hyperthyroidism is commonly referred to as factitious hyperthyroidism resulting from inappropriate intake of thyroid hormones. Moleculartargeted agents, thyroid hormone, interferon, and amiodarone are the most common drugs associated with hyperthyroidism [45]. Amiodarone is a common drug used to treat heart rhythm disorder. The high iodine content of the drug accelerates the thyroid gland to secrete excessive amounts of thyroid hormones [46]. Alemtuzumab an anti-cancerous drug induces hyperthyroidism in patients by producing autoantibodies against the thyroid gland and resulting in the development of Graves' disease. Another cancer drug PD-1 inhibitor used in cancer immunotherapy to boost the body's innate immune system results in the development of hyperthyroidism in patients by producing antibodies against thyroid hormones [47]. Highly active antiretroviral therapies, lithium, tyrosine kinase, and interferon α are other pharmaceutical compounds associated with drug-induced hyperthyroidism [48].

#### **6. Micronutrients in hyperthyroidism**

Nutritional factors are closely associated with regular physiological activities and optimal metabolic functioning. Dietary micronutrients are one of the predominant sources of essential micronutrients such as vitamins, minerals, trace elements, and amino acids [49]. Deficiency in these micronutrients results in great health concerns and according to the WHO, around 2 billion people are affected by micronutrient deficiency-related health disorders. Micronutrients mediate optimal metabolic functioning through the production of hormones, enzymes, and various biomolecules for optimal growth and development [50]. Despite being required in a small amount, a sensible deficiency of micronutrients results in detrimental effects on various physiological functioning such as regulating membrane permeability, enzymatic reactions, etc. [51]. Nutritional alterations are highly related to thyroid dysfunctions as the normal functioning of the thyroid is derived from optimal supplementation of various essential micronutrients.

The role of iodine and selenium in optimal production and proper metabolism of the thyroid is remarkable. Selenium-containing deiodinases play a pivotal role in the conversion of circulating T4 into physiologically active thyroid. The affinity of selenium-containing deiodinases toward specific receptors allows them to bind to receptors in nuclei, which in turn regulate gene expression. Selenium exists in the form of selenoproteins as functionally active. Glutathione peroxidase (GPX) and iodothyronine deiodinase are the two major enzymes with selenocysteine as an integral protein. Deiodinases generally exist in three forms, where 5′DII mediates the conversion of active thyroid hormone T3 from prohormone T4 and 5′DI catalyzes the degradation of rT3. The selenocysteine-containing deiodinase is involved in the

feedback and inactivates both thyroid hormones T4 and T3. Selenocysteine containing GPX protects the thyroid tissues from oxidative damage caused by hydrogen peroxide during the synthesis of thyroid hormone. The precursor of selenocysteine, monoselenium is also involved in the cellular defense mechanism.

The efficacy of iodine can be improved by supplementation of vitamin A, which results in vitamin A-mediated TSH-β suppression. The patients with severe iodine deficiency were observed with increased levels of TSH, thyroglobulin, and goiter size due to a deficiency of vitamin A [52]. Fluorine inhibits iodine transport and exhibits an anti-thyroid effect. Dietary intake of fluorine results in severe iodine deficiency and at higher concentrations, it might lead to goitrogenic [53]. The iodine transportation to the thyroid gland is inhibited by bromine, which results in physiological changes in the cellular architecture and affects the thyroid secretions [54]. Cobalt at higher concentrations results in goiter and affects thyroid hormone production, whereas cobalt deficiency reduces T3 levels. The function of selenium in thyroid functioning is well-studied in iodine transport [55]. Metal ions like cadmium, zinc, mercury, and rubidium tend to mimic the role of selenium or impart with selenium in iodine transport. Where these metals have various negative effects on thyroid functioning, as cadmium in rats has proven to increase levels of T3 and T4, and it also affects the activity of hepatic D1 [56]. Rubidium has been reported with inducing goiter in rats. Calcium has been reported to interfere with thyroid functioning, where excess dietary calcium results in goiter and is associated with low iodine clearance. Calcium also inhibits thyroxine adsorption [57, 58]. Asparagine and serine have been found to be positively correlated with the expression of TSH. Synthesis of T4 and FT4 were correlated with certain amino acids namely valine, leucine, and arginine, and the same was reported by Krishnamurthy *et al*., 2021.

#### **7. Antinuclear antibodies (ANA) in early diagnosis of hyperthyroidism**

Among the spectrum of autoimmune diseases, autoimmune thyroid diseases are the most common and are frequently associated with various organ-specific and non-organ-specific autoimmune disorders. Ani-thyroid peroxidase (Anti-TPO) and anti-thyroglobulin (Anti-Tg) are common markers of AITD. The prevalence of these anti-nuclear antibodies has been widely reported in AITD adult patients. ANA and other extractable antibodies are identified as novel diagnostic markers for predicting various autoimmune diseases. Over 90% of the patients with a multifactorial autoimmune disease such as systemic lupus erythematosus was detected with ANA. Various cross-sectional studies have reported the presence of ANA in healthy populations. A cross-sectional study by Satoh et al. [59] on 4754 individuals above 12 years reported the prevalence of ANA in 13.8% of the population. Another study by Hilário et al. [60] on healthy children reported the prevalence of ANA in 12.6% of the population. The rationale for the occurrence of these ANA remains unclear, but the assessment of these autoantibodies can be an early predictor of future autoimmune disorders.

Graves' disease and chronic lymphocytic thyroiditis are the most common organspecific autoimmune disorders resulting from lymphocytic infiltration of autoantibodies and thyroid hormones. A retrospective analysis by Siriwardhane et al. [61] evaluated the association of thyroid hormones TSH, FT4, and anti-TPO antibodies and anti-Tg. In this study, the presence of ANA and anti-ENA were evaluated in subjects with systemic autoimmune disease markers such as thyroid, anti-TPO, and anti-Tg. They reported a strong prevalence of ANA in 20.4% of thyroid positive subjects,

18.0%, and 17.6% in anti-TPO and anti-Tg positive subjects respectively. In their retrospective study, they exhibited a strong association between ATID markers and systemic autoimmune markers and the prevalence of anti-TPO and ANA and anti-ENA as specific markers for autoimmune thyroid disorders. This also suggests that periodical evaluation of ANA and other autoimmune antibodies would assist in the early detection of autoimmunity among individuals who have anti-TPO antibodies.

#### **8. Hyperthyroidism in human reproductive health**

Thyroid hormones are vital endocrine enzymes in maintaining regular metabolism and healthy reduction in both males and females. Alterations in thyroid synthesis have adverse effects on reproductive health. Sex steroids and sex-hormone-binding globulins are the prime metabolites associated with thyroid disorders. Both hyperthyroidism and hypothyroidism have considerable effects on reproductive health, whereas overactive thyroid is associated with various reproductive dysfunctions. In males, hyperactive thyroid results in impaired sexual behavior, a decrease in morphologically normal sperm, reduction in sperm motility and count. In females, thyroid imbalance mainly results in menstrual disturbances and reduced fertility. Hyperthyroidism is also associated with polymenorrhea and hypomenorrhea. A sharp increase in estrogen levels can be observed in hyperthyroid women and levels of SHBG were also found to increase. The production rate of testosterone and androstenedione was found to significantly increase in hyperthyroid women along with changes in androgen metabolism.

Hyperthyroidism in men is primarily characterized by elevated levels of SHBG resulting in increased levels of circulating total testosterone. Studies have reported that concentrations of free testosterone remain stable whereas the circulating levels of bioavailable testosterone were found to be depleted. Both total and free estradiol concentrations were found to decrease in hyperthyroid subjects. Overactive thyroid had adverse effects on semen quality, a study by Clyde et al. reported marked oligospermia resulting in low motility in two out of three hyperthyroid patients, where one was reported with low sperm count. A similar study by Kidd et al. in five hyperthyroid patients reported low sperm counts in all subjects.

A comprehensive retrospective analysis by Siriwardhane et al. analyzed the effects of altered thyroid hormones on vital sex hormones. The study with 15,043 subjects between the reproductive age of 15–49 years reported elevated levels of total testosterone and SHBG in hyperthyroid women. Anti-TPO seropositive women reported elevated testosterone and low cortisol. Whereas hyperthyroid men were reported with low DHEA-S and elevated estradiol, FSH, and prolactin. The study reported an inverse direction of SHBG levels in hyperthyroid and hypothyroid subjects in women. The positive correlation between SHBG with thyroid hormones FT3 and FT4 has been reported in various studies. The reduction in the metabolic clearance rate of testosterone due to the increased affinity between SHBG and testosterone increases the circulating levels of testosterone. This study also suggested that thyroid hormones could activate steroidogenesis in hyperthyroid patients resulting in increased levels of DHEA-S.

#### **9. Role of anti-TPO in early detection of hyperthyroidism**

Thyroid-specific auto-immune disorders are the second most organ-specific autoimmune disorder next to rheumatoid arthritis. Graves' disease and Hashimoto's thyroiditis are the most common thyroid-specific auto-immune disease. The pathogenesis of AITD includes various environmental and genetic factors. Anti-thyroid peroxidase is an antibody that synthesizes against a transmembrane of thyrocyte and is related to the levels of TSH which can be used to predict thyroid abnormalities. Over 90% of the cases with Hashimoto's thyroiditis and 80% of cases with Graves' disease are reported with the presence of anti-TPO. Anti-TPO antibodies in AITD subjects act as competitive inhibitors of thyroid activity and destroy thyrocytes. Anti-TPO antibodies highly belong to the IgG1 and IgG4 class of autoantibodies. Anti-TPO is an effective indicator of thyroid disease and also could indicate oxidative stress, advanced glycation, and oxygen metabolites in blood. Several studies have reported the presence of anti-TPO in Graves' disease, the recurrence of Graves' disease can be predicted by systemic evaluation of anti-TPO after anti-thyroid treatment [62].

A retrospective analysis by siriwardhane et al. reported the prevalence of anti-TPO as a selective marker for the early prediction of thyroid diseases. The results revealed the presence of anti-TPO prior to the onset of thyroid disease in both hyperthyroid and hypothyroid patients. The study also reported the occurrence of anti-TPO antibodies lacking any alterations in thyroid hormone levels. The study also reported that the anti-Tg antibody is a less specific marker for thyroid disease. A similar study by Hutfless et al. reported the prevalence of anti-TPO and anti-Tg antibodies 7 years prior to the diagnosis of Hashimoto's and Graves' disease. In summary, the thyroid system has a complex interplay with various factors including nutrition, autoimmunity, and reproductive function. Though some of these associations have been highlighted in the past decades, novel biochemistry and better diagnostic capabilities are unraveling novel associations that are leading to a more nuanced understanding of thyroid functions. This chapter explores some of these novel associations and sheds light on exciting outcomes that may arise in the years to come.

#### **Acknowledgments**

We acknowledge Vibrant America LLC for supporting this research.

### **Conflict of interest**

The authors declare no conflict of interest.

*Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.109375*

#### **Author details**

Hari Krishnan Krishnamurthy1 \* † , Swarnkumar Reddy2† , Vasanth Jayaraman1 , Karthik Krishna1 , Karenah E. Rajasekaran2 , Tianhao Wang1 , Kang Bei1 and John J. Rajasekaran1 \*

1 Vibrant Sciences LLC., San Carlos, CA, United States of America

2 Vibrant America LLC., San Carlos, CA, United States of America

\*Address all correspondence to: hari@vibrantsci.com and jjrajasekaran@vibrantsci.com

† These authors are joint senior authors on this work.

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Kravets I. Hyperthyroidism: Diagnosis and treatment. American Family Physician. 2016;**93**(5):363-370

[2] Taurog A. Hormone synthesis: Thyroid iodine metabolism. In: Werner and Ingbar's the Thyroid. Lippincott-Raven; 2000. pp. 61-85

[3] Rousset B, Dupuy C, Miot F, Dumont J. Thyroid hormone synthesis and secretion. Endotext. 2015;**2000**:2015

[4] Arthur JR, Beckett GJ. Thyroid function. British Medical Bulletin. 1999;**55**(3):658-668

[5] Tata JR, Widnell CC. Ribonucleic acid synthesis during the early action of thyroid hormones. Biochemical Journal. 1966;**98**(2):604

[6] Godswill AG, Somtochukwu IV, Ikechukwu AO, Kate EC. Health benefits of micronutrients (vitamins and minerals) and their associated deficiency diseases: A systematic review. International Journal of Food Sciences. 2020;**3**(1):1-32

[7] Kopp P. Human genome and diseases: Review the TSH receptor and its role in thyroid disease. Cellular and Molecular Life Sciences CMLS. 2001;**58**(9):1301-1322

[8] Galofré JC, Díez JJ, Cooper DS. Thyroid dysfunction in the era of precision medicine. Endocrinología y Nutrición (English Edition). 2016;**63**(7):354-363

[9] Siriwardhane T, Krishna K, Song Q, Ranganathan V, Jayaraman V, Wang T, et al. Human reproductive health in relation to thyroid alterations. Health. 2019;**11**(08):1095

[10] Lewis W. Hyperthyroidism and associated pathology. The Journal

of Nervous and Mental Disease. 1931;**74**(1):102

[11] Mathew P, Rawla P. Hyperthyroidism. StatPearls; 2022

[12] Delange F, De Benoist B, Alnwick D. Risks of iodine-induced hyperthyroidism after correction of iodine deficiency by iodized salt. Thyroid. 1999;**9**(6):545-556

[13] Leung AM, Braverman LE. Iodineinduced thyroid dysfunction. Current Opinion in Endocrinology, Diabetes, and Obesity. 2012;**19**(5):414

[14] van Hoek I, Hesta M, Biourge V. A critical review of food-associated factors proposed in the etiology of feline hyperthyroidism. Journal of Feline Medicine and Surgery. 2015;**17**(10):837-847

[15] Sajjadi-Jazi SM, Sharifi F, Varmaghani M, Meybodi HA, Farzadfar F, Larijani B. Epidemiology of hyperthyroidism in Iran: A systematic review and meta-analysis. Journal of Diabetes & Metabolic Disorders. 2018;**17**(2):345-355

[16] Siegel RD, Lee SL. Toxic nodular goiter: Toxic adenoma and toxic multinodular goiter. Endocrinology and Metabolism Clinics of North America. 1998;**27**(1):151-168

[17] Weetman AP. Graves' disease. New England Journal of Medicine. 2000;**343**(17):1236-1248

[18] Brent GA. Graves' disease. New England Journal of Medicine. 2008;**358**(24):2594-2605

[19] Burch HB, Cooper DS. Management of Graves disease: A review. JAMA. 2015;**314**(23):2544-2554

*Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.109375*

[20] Bartalena L. Diagnosis and management of graves disease: A global overview. Nature Reviews Endocrinology. 2013;**9**(12):724-734

[21] Prummel MF, Wiersinga WM. Smoking and risk of Graves' disease. JAMA. 1993;**269**(4):479-482

[22] Pearce EN, Farwell AP, Braverman LE. Thyroiditis. New England Journal of Medicine. 2003;**348**(26):2646-2655

[23] Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. The American Journal of Medicine. 2010;**123**(2):183-1e1

[24] Demirbilek HÜSEYİN, Kandemir NURGÜN, Gonc EN, Ozon A, Alikasifoglu A, Yordam NURŞEN. Hashimoto's thyroiditis in children and adolescents: A retrospective study on clinical, epidemiological and laboratory properties of the disease. Journal of Pediatric Endocrinology and Metabolism. 2007;**20**(11):1199-1206

[25] Ehlers M, Schott M. Hashimoto's thyroiditis and papillary thyroid cancer: Are they immunologically linked? Trends in Endocrinology & Metabolism. 2014;**25**(12):656-664

[26] Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinology and Metabolism Clinics. 2006;**35**(4):663-686

[27] Lania A, Sandri MT, Cellini M, Mirani M, Lavezzi E, Mazziotti G. Thyrotoxicosis in patients with COVID-19: The THYRCOV study. European Journal of Endocrinology. 2020;**183**(4):381-387

[28] Devereaux D, Tewelde SZ. Hyperthyroidism and thyrotoxicosis. Emergency medicine. Clinics. 2014;**32**(2):277-292

[29] Blick C, Nguyen M, Jialal I. Thyrotoxicosis. StatPearls Publishing; 2021

[30] Blick C, Schreyer KE. Gestational trophoblastic disease-induced thyroid storm. Clinical Practice and Cases in Emergency Medicine. 2019;**3**(4):409

[31] Aksoy DY, Gedik A, Cinar N, Soylemezoglu F, Berker M, Gurlek OA. Thyrotropinoma and multinodular goiter: A diagnostic challenge for hyperthyroidism. Journal of Research in Medical Sciences: The Official Journal of Isfahan University of Medical Sciences. 2013;**18**(11):1008

[32] Khalid N, Can AS. Plummer Disease. Treasure Island (FL): StatPearls Publishing 2021

[33] Mahajan, A., Ghaznavi, S.A., Lithgow, K. and Paschke, R., 2019. Toxic Multinodular Goiter

[34] Faggiano A, Del Prete M, Marciello F, Marotta V, Ramundo V, Colao A. Thyroid diseases in elderly. Minerva Endocrinologica. 2011;**36**(3):211-231

[35] De Leo S, Lee SY. Lewis E Braverman published in final edited form as. Lancet. 2016;**388**(10047):906-918

[36] LaFranchi S. Thyroiditis and acquired hypothyroidism. Pediatric Annals. 1992;**21**(1):29-39

[37] Batrinos ML. The problem of exogenous subclinical hyperthyroidism. Hormones Athens. 2006;**5**(2):119

[38] Toft AD. Subclinical hyperthyroidism. New England Journal of Medicine. 2001;**345**(7):512-516

[39] Biondi B, Palmieri EA, Klain M, Schlumberger M, Filetti S, Lombardi G. Subclinical hyperthyroidism: Clinical features and treatment options. European Journal of Endocrinology. 2005;**152**(1):1-9

[40] Roti E, Uberti ED. Iodine excess and hyperthyroidism. Thyroid. 2001;**11**(5):493-500

[41] Yang F, Teng W, Shan Z, Guan H, Li Y, Jin Y, et al. Epidemiological survey on the relationship between different iodine intakes and the prevalence of hyperthyroidism. European Journal of Endocrinology. 2002;**146**(5):613-618

[42] Martin FIR, Tress BW, Colman PG, Deam DR. Iodine-induced hyperthyroidism due to nonionic contrast radiography in the elderly. The American Journal of Medicine. 1993;**95**(1):78-82

[43] Beck-Peccoz P, Persani L, Mantovani S, Cortelazzi D, Asteria C. Thyrotropinsecreting pituitary adenomas. Metabolism. 1996;**45**:75-78

[44] Beck-Peccoz P, Persani L, Mannavola D, Campi I. TSH-secreting adenomas. Best Practice & Research Clinical Endocrinology & Metabolism. 2009;**23**(5):597-606

[45] Buchfelder M, Fahlbusch R. Thyrotroph adenomas. In: Diagnosis and Management of Pituitary Tumors. Totowa, NJ: Humana Press; 2001. pp. 333-342

[46] Atkins P, Cohen SB, Phillips BJ. Drug therapy for hyperthyroidism in pregnancy. Drug Safety. 2000;**23**(3):229-244

[47] Abraham P, Avenell A, Park CM, Watson WA, Bevan JS. A systematic review of drug therapy for graves'

hyperthyroidism. European Journal of Endocrinology. 2005;**153**(4):489-498

[48] Ekiz Bilir B, Soysal Atile N, Kirkizlar O, Kömürcü Y, Akpinar S, Sezer A, et al. Effectiveness of preoperative plasmapheresis in a pregnancy complicated by hyperthyroidism and anti-thyroid drugassociated angioedema. Gynecological Endocrinology. 2013;**29**(5):508-510

[49] Bassuk SS, Manson JE. Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. Journal of Applied Physiology. 2005;**2005**(3):1193-1204

[50] Hänsch R, Mendel RR. Physiological functions of mineral micronutrients (cu, Zn, Mn, Fe, Ni, Mo, B, cl). Current Opinion in Plant Biology. 2009;**12**(3):259-266

[51] Huskisson E, Maggini S, Ruf M. The influence of micronutrients on cognitive function and performance. Journal of International Medical Research. 2007;**35**(1):1-19

[52] Zimmermann MB, Jooste PL, Mabapa NS, Schoeman S, Biebinger R, Mushaphi LF, et al. Vitamin A supplementation in iodinedeficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate. The American Journal of Clinical Nutrition. 2007;**86**(4):1040-1044

[53] Galletti PM, Joyet G. Effect of fluorine on thyroidal iodine metabolism in hyperthyroidism. The Journal of Clinical Endocrinology & Metabolism. 1958;**18**(10):1102-1110

[54] Velický J, TItlbach M, Dušková J, Vobecký M, Štrbák V, Raška I. Potassium bromide and the thyroid gland of the rat: *Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.109375*

Morphology and immunohistochemistry, RIA and INAA analysis. Annals of Anatomy-Anatomischer Anzeiger. 1997;**179**(5):421-431

[55] Pimentel-Malaussena E, Roche M, Layrisse M. Treatment of eight cases of hyperthyroidism with cobaltous chloride. Journal of the American Medical Association. 1958;**167**(14):1719-1722

[56] Bach I, Braun S, Gati T, Kertai P, Sos J, Udvardy A. Effect of rubidium on the thyroid. In: Pitt-Rivers R, editor. Advances in Thyroid Research. New York: Pergamon Press; 1961

[57] Gupta P, Kar A. Role of ascorbic acid in cadmium-induced thyroid dysfunction and lipid peroxidation. In: Journal of Applied Toxicology: An International Forum Devoted to Research and Methods Emphasizing Direct Clinical, Industrial and Environmental Applications. Chichester: John Wiley & Sons, Ltd; 1998, September. pp. 317-320

[58] Paier B, Pavia MA Jr, Hansi C, Noli MI, Hagmüller K, Zaninovich AA. Cadmium inhibits the in vitro conversion of thyroxine to triiodothyronine in rat brown adipose tissue. Bulletin of Environmental Contamination and Toxicology. 1997;**59**(1):164-170

[59] Satoh M, Tanaka S, Ceribelli A, Calise SJ, Chan EK. A comprehensive overview on myositis-specific antibodies: New and old biomarkers in idiopathic inflammatory myopathy. Clinical Reviews in Allergy & Immunology. 2017;**52**:1-19

[60] Hilário MOE, Arnaldo LC, Campos RS, Teresa TM, Almeida G, Eduardo CAL. Frequency of antinuclear antibodies in healthy children and adolescents. Clinical Pediatrics. 2004;**43**(7):637-642

[61] Siriwardhane T, Krishna K, Ranganathan V, Jayaraman V, Wang T, Bei K, et al. Exploring systemic autoimmunity in thyroid disease subjects. Journal of Immunology Research. 2018;**2018**. Article ID 6895146

[62] Siriwardhane T, Krishna K, Ranganathan V, Jayaraman V, Wang T, Bei K, et al. Significance of anti-TPO as an early predictive marker in thyroid disease. Autoimmune Diseases. 2019;**2019**. Article ID 1684074

#### **Chapter 8**

## Surgery for Primary Hyperparathyroidism without Leaving a Visible Scar

*Elias Karakas and Stefan Schopf*

#### **Abstract**

Surgery for primary hyperparathyroidism changed significantly during the past decades, since localization procedures have been developed and became more and more reliable. Like in thyroid surgery, minimally invasive techniques are widely used. Furthermore, remote access techniques have evolved in thyroid surgery with the aim of optimizing cosmetic results by avoiding a visible scar on the neck. Transoral Endoscopic access *via* the vestibular approach (TOEPVA) is the newest remote access technique, also feasible and safe in parathyroid surgery with optimum cosmetic results.

**Keywords:** transoral, parathyroid, surgery, feasibility, safety, cosmesis

#### **1. Introduction**

Since the first operation for primary hyperparathyroidism (pHPT) surgery has been safely performed *via* an anterior neck incision. A better understanding of the underlying causes for pHPT in combination with evolving and improving localization procedures surgical approaches changed from the bilateral cervical exploration *via* a cervical skin incision to more and more focused and minimally invasive approaches [1].

These focused approaches are nowadays considered as the new gold standard in localized pHPT [2].

In most patients, wound healing is without any problems, especially after a skin incision of less than 2 cm (**Figure 1**). However, a worldwide consideration of potential wound healing problems may lead to a more differentiated appraisal (**Figure 2**). In African countries, for example, the incidence of keloid development after skin incision is up to 15% and in some countries, a scar on the neck is historically related to a negative standing.

Also, in western countries, nearly 20% of patients will experience some feelings of self-consciousness years after open neck surgery. More than 10% will consider further treatments such as plastic surgery to their cervical scars [3]. The impact of a the cervical incision on the health-related quality of life (HRQOL) was found to be like the impact of vitiligo, psoriasis, or severe atopic dermatitis in one series [4, 5]. Foremost in the thyroid but also in parathyroid surgery remote access surgery has evolved with the aim to optimize cosmesis [6].

**Figure 1.** *Minimal almost 2 cm skin incision in focused parathyroid surgery.*

**Figure 2.** *Keloid in a small cervical scar.*

Remote access surgery includes the areolar or axillary or combined areolar/ axillary (ABBA) incisions and the retroauricular approach, which can effectively minimize the cosmetic burden on some patients. Improved cosmesis on one hand but unfamiliar dissection planes, longer routes to the central neck, and novel complications, on the other hand lead to further investigations focusing on the so-called natural orifice approaches. The emerging transoral thyroid and parathyroid vestibular approach—TOETVA in thyroid and TOEPVA in parathyroid surgery—was inspired by the idea to follow the embryologic thyroglossal duct. While feasibility was proven in substantial experimental and preclinical investigations by different study groups since 2006 and the first transoral parathyroid resection was done in 2010 [7], the clinical proof of concept was given by Anuwong, who published the

*Surgery for Primary Hyperparathyroidism without Leaving a Visible Scar DOI: http://dx.doi.org/10.5772/intechopen.110691*

first case series of 60 patients who underwent scarless thyroidectomy *via* the lower vestibule of the mouth with excellent outcomes [8]. This was followed by the first series of transoral transvestibular parathyroid operations with also promising results by Sasanakietkul et al. [9].

TOEPVA can be performed for select patients with localized primary hyperparathyroidism (HPT). Those without parathyroid adenoma localization, recurrent or persistent primary HPT, suspected multigland disease, secondary or tertiary HPT, family history of MEN, suspected parathyroid carcinoma, or previous central neck surgery or neck irradiation therapy should be excluded from consideration. Similar to TOETVA, the patient should also be highly motivated for a "scarless" approach.

#### **2. TOEPVA: parathyroid surgery without leaving a visible scar**

#### **2.1 History of parathyroid surgery**

Over more than 50 years bilateral cervical exploration (BCE) was the gold standard in parathyroid surgery. All parathyroids are visualized to resect the macroscopically enlarged gland [10]. BCE is associated with a more than 95% cure rate and minimal morbidity in experienced hands. In these times "the only localization that a patient needs who has primary hyperparathyroidism is the localization of an experienced surgeon!" [11]. Because primary HPT is a single gland disease in more than 80% and preoperative localization procedures have emerged and improved during the past decades minimally invasive procedures have been developed to minimize cervical skin incisions. These less invasive operations offer similar cure rates and result in equal complications compared to open surgery [12–14]. Minimally invasive parathyroidectomy leads to lower hospital costs, shorter length of stay, and equally high cure rates with low complication rates [15, 16].

#### **2.2 Prerequisites, patients, and surgical technique**

Surgeons interested in performing transoral parathyroid surgery should be well-experienced in parathyroid surgery. In addition, experience with laparoscopic instrumentation is beneficial. The transoral technique should be trained within cadaver courses meanwhile frequently offered in specialized centers. Subsequently, the first transoral operations in the clinical setting should ideally performed with the assistance of an experienced transoral surgeon. The suspected parathyroid gland should be safely detected in one, better two preoperative localization procedures.

The transoral procedure should safely be implemented in patients with small thyroid specimens and benign thyroid nodules <20 mm in diameter.

#### **2.3 Postoperative recommendations**

In case of recurrent laryngeal nerve palsy (RLNP), patients should be reevaluated 1 week and/or 4 weeks after surgery and, if necessary, logopedics should be initiated with reevaluation 3 and 6 months after surgery.

Potential paresthesia in the chin area and lower lip due to mental nerve injury should carefully be documented postoperatively during a hospital stay. In case of persistent paresthesia, patients should be reevaluated 3, 6, and 12 months after surgery. In addition, patients should be introduced to grimace and repeatedly activate their mimic muscles directly after surgery.

Serum Calcium (Ca) as well as parathyroid hormone (PTH) levels should be measured pre- and postoperatively on day one to prove the success of the operation. To exclude persistence Ca levels should be monitored for 6 months. In case of low vitamin D levels and potential bone involvement Ca and vitamin D should be provided.

### **3. TOEPVA technique step by step**

#### **3.1 Surgical technique**

Patients are placed in a supine position with a slight neck extension (**Figure 3a**). The use of intraoperative nerve monitoring (IONM) is strongly recommended. The endotracheal tube provided with an electrode for IONM can easily be placed transorally. A transnasal tube placement is not necessary (**Figure 3b**).

The mucosa of the oral cavity should be cleansed with chlorhexidine solution. Afterward, three small incisions, 1–1.5 cm in the midline and 5 mm lateral right and left are made in the lower lip as close to the lip vermilion and as far away from the branches of the mental nerve as possible (**Figures 4a** and **b**).

Afterward, a subplatysmal space is created by hydro-dissection using an epinephrine-enriched saline solution injected with a Verress needle. The subplatysmal space is widened using a blunt dissector (**Figures 5a, b** and **c**).

Three trocars (originally one 10 mm and two 5 mm in diameter) are inserted through the midline and lateral incisions, followed by high-flow CO2 gas insufflation at a maximum pressure of 8 mmHg (**Figure 6**).

**Figure 3a.** *Patient's positioning with eye protection.*

*Surgery for Primary Hyperparathyroidism without Leaving a Visible Scar DOI: http://dx.doi.org/10.5772/intechopen.110691*

**Figure 3b.** *Transoral tube placement and disinfection of the mucosa.*

**Figure 4a.** *Midline incision close to the lip vermilion to avoid mental nerve injury.*

**Figure 4b.** *Cadaver study regarding trocar placement and mental nerve branches.*

**Figure 5a.** *Application of epinephrine enriched saline solution with Verres needle to create an artificial subplatysmal space.*

*Surgery for Primary Hyperparathyroidism without Leaving a Visible Scar DOI: http://dx.doi.org/10.5772/intechopen.110691*

**Figure 5b.** *Blunt dissection of the artificial subplatysmal space.*

**Figure 5c.** *Artificial subplatysmal space.*

Either a 5 mm or a 10 mm 30° full HD camera is used as well as conventional laparoscopic instruments. The subplatysmal working space reaches from the thyroid cartilage to the sternal notch and the medial border of both sternocleidomastoid muscles.

**Figure 6.** *Trocar placement—3 trocars 5 mm in the vestibulum oris.*

**Figure 7.** *Division of the strap muscles in the midline with a sealing device.*

The strap muscles are divided in the midline and the lateral space of the assumed side will be dissected (**Figure 7**). In addition to gas insufflation two stitches are placed from outside to retract the strap muscles ventrally and laterally to optimize the working space (**Figure 8**).

Vessels should be selectively sealed with a thermal device. As in minimally invasive open surgery, the RLN does not routinely be visualized in case of a lower *Surgery for Primary Hyperparathyroidism without Leaving a Visible Scar DOI: http://dx.doi.org/10.5772/intechopen.110691*

**Figure 8.** *Retracted muscles and lateral dissection.*

#### **Figure 9.**

*Localization and identification of a parathyroid gland with indocyanine green fluorescent agent. (with courtesy of Prof. Philip Riss university hospital Vienna, Austria).*

parathyroid adenoma. In addition, parathyroid glands can be visualized using fluorescent agents (**Figure 9**).

The resected parathyroid specimen is extracted through the midline trocar access. Strap muscles are not adapted routinely at the end of the operation. Oral mucosa as well as retroauricular skin incision are closed using a 4/0 absorbable suture.

### **4. Conclusion**

Transoral parathyroid surgery is feasible and save. As in conventional open minimal invasive surgery experience of the surgeon in parathyroid surgery and positive preoperative localization is essential.

### **Acknowledgements**

We thank the EUROPEAN Study Group for Transoral Surgery, especially Prof. Philipp Riss and Prof. Christian Scheuba for providing figures regarding the use of fluorescend agents in transoral parathyroid surgery.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Elias Karakas1 and Stefan Schopf<sup>2</sup> \*

1 Hospital Maria Hilf, Alexianer GmbH, Krefeld, Germany

2 RoMed Hospital Bad Aibling, Germany

\*Address all correspondence to: stefan.schopf@ro-med.de

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Surgery for Primary Hyperparathyroidism without Leaving a Visible Scar DOI: http://dx.doi.org/10.5772/intechopen.110691*

#### **References**

[1] Miccoli P, Bendinelli C, Berti P, Vignali E, Pinchera A, Marcocci C. Videoassisted versus conventional parathyroidectomy in primary hyperparathyroidism: A prospective randomized study. Surgery. 1999;**126**(6):1117-1122

[2] Ahmadieh H, Kreidieh O, Akl EA, El-Hajj FG. Minimally invasive parathyroidectomy guided by intraoperative parathyroid hormone monitoring (IOPTH) and preoperative imaging versus bilateral neck exploration for primary hyperparathyroidism in adults. Cochrane Database of Systematic Reviews. 2020;(10). Art. No.: CD010787. DOI: 10.1002/14651858.CD010787.pub2

[3] Best AR, Shipchandler TZ, Cordes SR. Midcervical scar satisfaction in thyroidectomy patients. The Laryngoscope. 2017;**127**:1247-1252. DOI: 10.1002/lary.26177

[4] Choi Y, Lee JH, Kim YH, et al. Impact of postthyroidectomy scar on the quality of life of thyroid cancer patients. Annals of Dermatology. 2014;**26**:693-699. DOI: 10.5021/ad.2014.26.6.693

[5] Arora A, Swords C, Garas G, et al. The perception of scar cosmesis following thyroid and parathyroid surgery: A prospective cohort study. International Journal of Surgery. 2016;**25**:38-43. DOI: 10.1016/j.ijsu.2015.11.021

[6] Berber E, Bernet V, Fahey TJ 3rd, et al. American thyroid association statement on remote-access thyroid surgery. Thyroid. 2016;**26**:331-337. DOI: 10.1089/ thy.2015.0407

[7] Karakas E, Steinfeldt T, Gockel A, Schlosshauer T, Dietz C, Jäger J, et al. Transoral thyroid and parathyroid

surgery–development of a new transoral technique. Surgery. 2011;**150**(1):108-115. DOI: 10.1016/j.surg.2010.12.016

[8] Anuwong A. Transoral endoscopic thyroidectomy vestibular approach: A series of the first 60 human cases. World Journal of Surgery. 2016;**40**:491-497. DOI: 10.1007/s00268-015-3320-1

[9] Sasanakietkul T, Jitpratoom P, Anuwong A. Transoral endoscopic parathyroidectomy vestibular approach: A novel scarless parathyroid surgery. Surgical Endoscopy. 2017;**31**:3755-3763. DOI: 10.1007/s00464-016-5397-5

[10] Chen H. Annals of Surgery;**236**(5):552-553

[11] Brennan MF, Doppman JL, Marx SJ, Spiegel AM, Brown EM, Aurbach GD. Reoperative parathyroid surgery for persistent hyperparathyroidism. Surgery. 1978;**83**(6):669-676

[12] Tibblin S, Bondeson A, Ljungberg O. Annals of Surgery. 1982;**195**(3):245-252

[13] Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Annals of Surgery. 2002;**235**:665-670

[14] Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Annals of Surgery. 2000;**232**:331-339

[15] Bergenfelz A, Kanngiesser V, Zielke A, Nies C, Rothmund M. Conventional bilateral cervical exploration versus open minimally invasive parathyroidectomy under local anaesthesia for primary hyperparathyroidism. The British Journal of Surgery. 2005;**92**(2):190-197. DOI: 10.1002/bjs.4814

*Hyperthyroidism - Recent Updates*

[16] Karakas E, Schneider R, Rothmund M, Bartsch DK, Schlosser K. Initial surgery for benign primary hyperparathyroidism: An analysis of 1,300 patients in a teaching hospital. World Journal of Surgery. 2014;**38**(8):2011-2018. DOI: 10.1007/ s00268-014-2520-4

### *Edited by Volkan Gelen, Abdulsamed Kükürt and Emin Şengül*

Hyperthyroidism is a condition caused by physiological, biological, and clinical findings that cause hypermetabolism as a result of the excessive elevation of thyroid hormones in the blood and the surrounding tissues under the influence of high levels of hormones. There is a general acceleration in metabolism. There are a wide variety of methods in the treatment of hyperthyroidism, such as antithyroid drugs, lithium carbonate, radioactive iodine, and dexamethasone. This comprehensive book, with contributions from various researchers on thyroid hormones and hyperthyroidism, offers a wide range of expert reviews on the release of thyroid hormones, their physiological effects, and the occurrence of hyperthyroidism as well as its types, effects, and treatment options.

Published in London, UK © 2023 IntechOpen © Pierell / iStock

Hyperthyroidism - Recent Updates

Hyperthyroidism

Recent Updates

*Edited by Volkan Gelen,* 

*Abdulsamed Kükürt and Emin Şengül*