**3. Pathophysiology of storm**

In order to understand the pathophysiology and rationale of treatment for thyroid storm, we need to understand the normal thyroid hormone physiology. Normal thyroid function is under control of feedback mechanisms between the hypothalamus, anterior pituitary and thyroid gland. "Thyrotropin-releasing hormone" (TRH) stimulates anterior pituitary to release "thyroid-stimulating hormone" (TSH), which binds to its receptor on thyroid gland and stimulates the synthesis and secretion of thyroid hormone. The thyroid hormone synthesis is a five-step process comprising of: (a) iodide trapping; (b) organification—oxidation and iodination; (c) coupling; (d) storage; and (e) release. Transport of iodide into the thyroid follicular cell via a sodium-iodide symporter is the first step in hormone synthesis, known as "iodide trapping." Iodide is then "oxidized and organified" by thyroid peroxidase enzyme (TPO). Iodination of tyrosine residues on thyroglobulin (framework protein for thyroid hormone synthesis) is catalyzed by TPO forming thyroxine (T4) and triiodothyronine (T3). Thyroid hormone acts through intranuclear action of T3 with T4 acting more as a "prohormone" [15]. Twenty percent of T3 comes directly from thyroid gland and 80% of circulating T3 comes from peripheral conversion of T4 to T3. The entire process is controlled by a negative feedback loop with peripheral thyroid hormone inhibiting the release and synthesis of TSH and TRH. Majority of the thyroid hormone is protein-bound (>99%) to thyroid-binding globulin (TBG), transthyretin, and albumin [16] making a "circulating storage pool," while unbound or free hormone is available for uptake into the tissues.

Peripheral conversion of T4 to T3 is done by the 5′-deiodinases. The deiodinase D2 is active in euthyroid state whereas in hyperthyroid state deiodinase D1 is more prevalent. The deiodinase D1 is susceptible to inhibition by thionamide and propylthiouracil (PTU). Glucocorticoids and β-blockers inhibit peripheral conversion of T4 to T3. This understanding will help us understand the rationale behind use of various classes of drugs in the treatment of thyroid storm.

Exact pathophysiology of thyroid storm is poorly understood. Several hypotheses have been postulated for the storm, which are as follows:

### **3.1 Acute increase in release of T4 or T3 from thyroid gland**

It is the most important mechanism behind thyroid storm [17]. Acute increase in T4 or T3 hormones is seen after radioiodine therapy, thyroidectomy, discontinuation of antithyroid drugs, and administration of iodinated contrast agents or iodine [18]. Rapid improvements in clinical condition after reduction in T4 or T3 concentration after peritoneal dialysis or plasmapheresis support this theory [19].

### **3.2 Acute illness causes decrease in protein binding of T4 and T3 in serum resulting in increase of free T4 and T3**

Acute illnesses lead to decrease in protein binding of T4 and T3 [20], either due to decrease in production of transthyretin or due to production of inhibitors of T4- and T3-binding protein [21]. They lead to decrease in bound form of T4 and T3,

**117**

**Table 1.**

*Thyroid Storm: Clinical Manifestation, Pathophysiology, and Treatment*

**3.4 Augmentation of cellular responses to thyroid hormone**

**Common Rare**

**3.3 Role of sympathetic nervous system activation**

which ultimately leads to relative increase in serum concentration of the hormones,

Many symptoms and signs of thyroid storm mimic those of catecholamine excess, suggesting the role of sympathetic nervous system activation [23]. Dramatic improvement in symptoms following beta blocker administration supports this

In patients with condition of hypoxemia, ketoacidosis, lactic acidosis, and infection, there is augmentation of cellular response to thyroid hormone [25]. There is uncoupling of oxidative phosphorylation leading to generation of ATP, which results in excess utilization of substrate, increased oxygen consumption, thermogenesis, and hyperthermia [26]. Excess heat is dissipated by increased sweating and

cutaneous vasodilation, the most common symptoms of thyroid storm.

The transition from simple thyrotoxicosis to thyrotoxic crisis requires a superimposed insult. Any primary cause of hyperthyroidism can escalate into thyrotoxic crisis. There are triggers that can induce thyroid storm in patients with unrecognized thyrotoxicosis, which includes nonthyroidal surgery, parturition, major trauma, infection, or iodine exposure from radiocontrast dyes or amiodarone [27]. Common and rare triggers are listed in **Table 1**. Infection is the most common precipitant of thyroid storm in the hospitalized patients [3, 17, 27, 28]. There is no identifiable precipitating factor in about 25–43% of patients of storm [29].

Infection [6] Vigorous palpation of thyroid gland [30]

Acute medical illness Subacute thyroiditis [31] Acute psychosis [32] Thyroxine overdosage [33] Nonthyroidal surgery [18] Aspirin intoxication [34] Parturition [35] Hydatidiform mole [36] Trauma [37] OP poisoning [38] Discontinuation of antithyroid drugs [39] Neurotoxins [40]

After radioactive iodine therapy [41] Cytotoxic chemotherapy [42]

The diagnosis of thyroid storm is purely clinical, and if suspected, treatment should be initiated simultaneously without any delay. Clinical picture comprises

*DOI: http://dx.doi.org/10.5772/intechopen.89620*

which causes storm [22].

**4. Triggers of thyroid storm**

**5. Clinical features and diagnosis**

After high dose of iodine administration [44] Iodinated radiographic contrast agents [45]

Post-thyroidectomy [43]

*Triggers of thyroid storm.*

hypothesis [24].

which ultimately leads to relative increase in serum concentration of the hormones, which causes storm [22].
