Hyperthyroidism: A Clinical Review
Definition
Hyperthyroidism is a clinical and biochemical syndrome resulting from the excessive synthesis and secretion of thyroid hormones—thyroxine (T4) and triiodothyronine (T3)—by the thyroid gland itself, leading to a systemic hypermetabolic state (1, 8). It is crucial to distinguish this from thyrotoxicosis, which is a broader term describing the clinical state of excess thyroid hormone in the tissues, regardless of the source (1). While hyperthyroidism is the most common cause of thyrotoxicosis, the latter also includes conditions where hormones are passively released from a damaged gland (e.g., thyroiditis) or introduced from an external source (e.g., factitious thyrotoxicosis). This distinction is not merely academic; it is the first critical branch point in diagnosis. Misclassifying a destructive thyroiditis as true hyperthyroidism could lead to the inappropriate and ineffective use of antithyroid drugs, which only work by blocking new hormone synthesis (12).
Epidemiology
Thyroid dysfunction is the second most common endocrine disorder in Malaysia after diabetes mellitus, representing a significant public health issue (27). The overall prevalence of hyperthyroidism in the Malaysian adult population is 3.4%. This figure is composed of two distinct clinical entities: 0.5-0.6% overt hyperthyroidism, where patients are typically symptomatic, and a much larger proportion of 2.8% subclinical hyperthyroidism, where patients may be asymptomatic (13, 15). This large reservoir of subclinical disease is particularly concerning in Malaysia's aging population, as untreated subclinical hyperthyroidism is a known risk factor for developing atrial fibrillation and osteoporosis (7).
The condition shows a marked female predominance, with women being 5 to 10 times more likely to be affected than men, a disparity largely attributed to the higher prevalence of autoimmune diseases in females (28). The typical age of onset is between 20 and 50 years, especially for Graves' disease (13). While some regional Malaysian studies suggest a higher prevalence among the Malay population, other broader nationwide data indicate no statistically significant difference among the country's major ethnicities (13, 15, 38). This suggests that geographic factors, such as the historical iodine status in remote inland areas versus coastal regions, and environmental triggers may be more influential in disease development than ethnicity alone.
Etiology
The causes of hyperthyroidism are varied, but a few key etiologies predominate in the Malaysian clinical setting. A clear understanding of these causes is essential for guiding investigations.
Graves' Disease (GD): This autoimmune condition is the most common cause, accounting for 50-80% of all cases of thyrotoxicosis. It is responsible for 57.7% of cases referred for radioactive iodine therapy in a Northern Malaysian cohort (13, 26). GD is triggered by a combination of genetic susceptibility and environmental factors, such as stress, infection, and notably, smoking, which is a strong risk factor for both the onset of GD and the development of its most severe eye complications (13).
Toxic Nodular Disease: This category includes Toxic Multinodular Goitre (TMNG) and the solitary Toxic Adenoma (TA). It is the second most common cause, particularly in individuals over 50 and in regions with historical iodine deficiency. One Malaysian study found it accounted for a significant 42.3% of cases in their cohort (6, 13). This condition represents the end stage of a long process where chronic TSH stimulation (often from iodine deficiency) leads to goiter formation, followed by the development of autonomous nodules that produce hormones independent of pituitary control.
Thyroiditis: This involves inflammation of the gland, leading to the destruction of thyroid follicles and a transient release of pre-formed hormone. It classically follows a triphasic course: an initial hyperthyroid phase, followed by a hypothyroid phase as hormone stores are depleted, and eventual recovery to a euthyroid state. Important types include:
Subacute (de Quervain's) Thyroiditis: Often follows a viral upper respiratory tract infection and is characterized by a markedly painful, tender goiter (12).
Postpartum Thyroiditis (PPT): A crucial diagnosis to consider in any woman presenting with thyrotoxicosis within the first year after childbirth, resulting from immunologic rebound after delivery (12).
Drug-Induced Hyperthyroidism: Certain medications are well-known culprits. Amiodarone, an iodine-rich antiarrhythmic, is a major cause and can induce two types of thyrotoxicosis: Type 1 (Jod-Basedow effect in patients with underlying nodules) and Type 2 (a destructive thyroiditis) (6). Iodinated contrast media and Lithium can also induce thyrotoxicosis (6, 11).
Exogenous/Factitious Thyrotoxicosis: This occurs from the intentional or accidental ingestion of excessive thyroid hormone medication, which should be suspected in patients with thyrotoxicosis but a non-palpable thyroid gland and low thyroglobulin levels (4).
Pathophysiology
The pathophysiology of hyperthyroidism involves a disruption of the elegant negative feedback loop of the Hypothalamic-Pituitary-Thyroid (HPT) axis. In a healthy state, the pituitary releases TSH, which stimulates the thyroid. The resulting T3/T4 then signal back to the pituitary and hypothalamus to inhibit further TSH release. In primary hyperthyroidism, this control system is overridden.
Graves' Disease: The core mechanism is the production of TSH Receptor Antibodies (TRAb) by the immune system. Specifically, stimulated T-lymphocytes cause B-lymphocytes to produce these antibodies. TRAb mimics the action of TSH, binding to and continuously activating the TSH receptor on thyroid follicular cells. This leads to two key outcomes: uncontrolled, excessive hormone production (hormonogenesis) and diffuse growth of the gland (hyperplasia), resulting in a smooth, vascular goiter, all of which occurs independent of pituitary control (21).
Toxic Nodular Disease: This arises from somatic mutations in the TSH receptor gene within proliferating thyroid follicular cells. These mutations cause the receptor to become "constitutively active," meaning they are permanently switched on. The affected cells begin to produce thyroid hormone autonomously. As these nodules grow, the rising T3/T4 levels exert negative feedback on the pituitary, suppressing TSH. This low TSH "switches off" the normal, non-autonomous thyroid tissue, but the "hot" nodules, which are no longer TSH-dependent, continue to hyper-secrete hormones (1).
Systemic Effects: Excess thyroid hormone induces a profound hypermetabolic and hyperadrenergic state.
Metabolic: It increases the basal metabolic rate in all tissues, leading to increased oxygen consumption, protein turnover, and heat production. This manifests as weight loss despite increased appetite, heat intolerance, and profound fatigue (4).
Cardiovascular: It increases the number and sensitivity of beta-adrenergic receptors on myocardial cells, amplifying the effects of catecholamines. This leads to increased heart rate (tachycardia), increased force of contraction (inotropism), and increased cardiac output. Chronically, this can lead to high-output heart failure (8).
Neurological: The hyperadrenergic state causes nervousness, anxiety, and a characteristic fine tremor. Deep tendon reflexes are brisk with a notably rapid relaxation phase (4).
Skeletal: Thyroid hormone directly stimulates osteoclasts, accelerating bone resorption more than bone formation. This net loss of bone mass leads to decreased bone mineral density and a significantly increased risk of osteoporosis and fragility fractures (7).
Clinical Presentation
The clinical picture reflects the systemic effects of hormone excess. Always start with a thorough history and physical examination to look for classic signs and symptoms.
Diagnostic Clues
Pathognomonic Signs of Graves' Disease: Their presence can confirm the diagnosis at the bedside, often making further etiological investigation unnecessary.
Graves' Orbitopathy (GO): Found in 25-50% of GD patients (34.7% in Malaysian patients), this is an autoimmune inflammation of the retro-orbital tissues. Signs can be remembered with the mnemonic NO SPECS: No signs or symptoms; Only signs (lid retraction, stare); Soft tissue involvement (periorbital edema); Proptosis; Extraocular muscle involvement (diplopia); Corneal involvement; Sight loss (optic nerve compression) (8, 38).
Pretibial Myxedema (Thyroid Dermopathy): A rare (1.5%) finding of hardened, non-pitting, often discolored (violaceous or brown) plaques on the shins, with a characteristic "peau d'orange" (orange peel) texture (5).
Thyroid Acropachy: The rarest sign (0.3%), presenting as digital clubbing and soft tissue swelling of the hands and feet, which can resemble hypertrophic osteoarthropathy (8).
Common Symptoms (>50%)
Constitutional: Unexplained weight loss despite a normal or even voracious appetite (polyphagia), debilitating fatigue, and a profound heat intolerance, often causing patients to wear lighter clothing than others and prefer cold environments (1).
Cardiovascular: Palpitations, often described as a "racing" or "pounding" heart, and sinus tachycardia (resting heart rate >90-100 bpm) are near-universal complaints (5).
Neurological: A persistent feeling of being "on edge," with nervousness, anxiety, emotional lability, and a fine tremor of the outstretched hands and fingers (4).
Goiter: An enlarged thyroid gland. In Graves' disease, it is typically diffuse, smooth, and may have an audible bruit on auscultation due to high vascularity. In TMNG, it feels nodular or "lumpy" (4).
Less Common Symptoms (10-50%)
Gastrointestinal: Increased gut motility leading to more frequent bowel movements (hyperdefecation) or, less commonly, true diarrhea with malabsorption (5).
Musculoskeletal: A proximal myopathy causing weakness in the shoulder and pelvic girdles, manifesting as difficulty climbing stairs, rising from a chair, or combing hair (5).
Reproductive: Menstrual irregularities in females, such as lighter periods (oligomenorrhea) or absent periods (amenorrhea) (5).
Ocular (Non-infiltrative): Lid lag (von Graefe's sign), where the upper eyelid lags behind the eyeball on downward gaze, and a "staring" or "startled" appearance (Dalrymple's sign) due to adrenergic overstimulation of the eyelid muscles (8).
⚠️ Red Flag Signs & Symptoms
Thyroid Storm: A life-threatening endocrine emergency. Suspect in any thyrotoxic patient with high fever (>38.5°C), severe CNS dysfunction (agitation, delirium, psychosis, coma), and evidence of cardiovascular collapse or GI-hepatic dysfunction (12). The Burch-Wartofsky Point Scale can be used to quantify risk.
Thyrotoxic Periodic Paralysis (TPP): Presents as acute, flaccid muscle paralysis accompanied by severe hypokalemia. It is a crucial differential for any young Asian male presenting with acute weakness, as this demographic has a higher prevalence of the underlying ion channel mutations that are triggered by the thyrotoxic state (13).
Severe Graves' Orbitopathy: Signs of optic nerve compression such as decreased visual acuity, changes in color vision (desaturation), or a visual field defect require an urgent ophthalmology referral to prevent permanent vision loss (16).
Complications
Untreated or poorly controlled hyperthyroidism can lead to severe, multi-systemic complications.
Cardiovascular: Atrial fibrillation (occurs in 10-15% of patients) is a major risk, as excess thyroid hormone shortens the atrial refractory period, promoting re-entrant arrhythmias. This significantly increases the risk of thromboembolic stroke. Chronic tachycardia and increased cardiac output can lead to high-output heart failure and dilated cardiomyopathy (5, 8).
Skeletal: Osteoporosis and an increased risk of fragility fractures are significant long-term complications. Excess thyroid hormone directly stimulates osteoclast activity, leading to accelerated bone resorption that outpaces bone formation, resulting in a net loss of bone mass (7).
Neurological: In its most severe form (thyroid storm), complications include seizures and coma. Chronic anxiety, mood disorders, and cognitive impairment can also occur (8).
Pregnancy-related: In pregnant women, uncontrolled hyperthyroidism is associated with a higher risk of miscarriage, pre-eclampsia, preterm birth, and low birth weight. The fetus is also at risk of thyrotoxicosis if maternal TRAb levels are high (14).
Psychological: The impact on quality of life can be profound, with patients suffering from severe anxiety, irritability, mood swings, and an inability to concentrate, affecting work, relationships, and daily functioning.
Prognosis
With timely diagnosis and appropriate treatment, the prognosis for patients with hyperthyroidism is generally excellent. For Graves' disease treated with a standard course of antithyroid drugs (ATDs) for 12-18 months, the remission rate is approximately 50%. Factors predicting relapse include large goiter size, high TRAb levels at the end of therapy, and smoking. Patients who relapse require definitive therapy (16). For toxic nodular disease, spontaneous remission does not occur; definitive treatment with radioactive iodine (RAI) or surgery is necessary for a cure, after which the prognosis is very good, although lifelong levothyroxine replacement is usually required (12). Thyroid storm, however, remains a highly lethal condition, with a mortality rate of 10-30% even with modern intensive care (12).
Differential Diagnosis
Anxiety Disorders: These conditions share symptoms like palpitations, tremor, and anxiety. However, patients with anxiety disorders will not have the physical signs of thyrotoxicosis like goiter, ophthalmopathy, or weight loss despite polyphagia. A suppressed TSH and elevated free T4/T3 will confirm a thyroid etiology.
Pheochromocytoma: This rare catecholamine-secreting adrenal tumor also causes hyperadrenergic symptoms. However, it is characterized by the classic triad of episodic headaches, sweating, and palpitations, often with paroxysmal and severe hypertension. The diagnosis is confirmed by measuring plasma or 24-hour urinary metanephrines, not by abnormal TFTs.
Thyroiditis vs. Graves' Disease: Both cause thyrotoxicosis, but the management is fundamentally different. A history of recent viral illness, neck pain, and a markedly tender goiter on examination strongly suggests subacute thyroiditis. Thyroiditis is a state of hormone leakage, not overproduction, and will therefore result in low or absent uptake on a RAIU scan, whereas Graves' disease shows high, diffuse uptake (6, 11).
Substance Abuse: The use of stimulants such as cocaine or amphetamines can mimic the hyperadrenergic state of thyrotoxicosis, causing tachycardia, sweating, and anxiety. A thorough social history and urine toxicology screen can help differentiate these conditions.
Investigations
A stepwise approach is crucial to confirm the diagnosis, establish the etiology, and monitor treatment safely and cost-effectively.
Immediate & Bedside Tests
ECG: Mandatory in all symptomatic patients to detect sinus tachycardia or, more importantly, arrhythmias like atrial fibrillation, which requires anticoagulation. It can also assess for signs of cardiac ischemia, as the high metabolic demand can unmask underlying coronary artery disease (5).
Diagnostic Workup
First-Line Investigations (Biochemical Confirmation):
"The initial tests of choice are serum TSH and fT4, as mandated by the Malaysian CPG (6). A suppressed TSH with an elevated fT4 provides biochemical confirmation of overt primary hyperthyroidism (the rationale), giving a clear mandate to proceed with etiological investigation (the action)."
"If the TSH is suppressed but the fT4 is within the normal range, a serum fT3 must be measured to diagnose or exclude T3-toxicosis (the rationale). This is crucial as T3-toxicosis can be the initial presentation of Graves' disease or toxic nodules and would be missed otherwise (the action) (6)."
Etiological Workup:
TSH Receptor Antibody (TRAb): "This blood test is the key investigation when Graves' disease is suspected but not clinically obvious (e.g., no clear orbitopathy). A positive TRAb result is highly specific for Graves' disease (the rationale), confirming the autoimmune etiology, often avoiding the need for further imaging, and providing prognostic information about the likelihood of remission (the action) (16)."
Thyroid Ultrasound with Doppler: "Ultrasound is essential to structurally evaluate palpable nodules or when scintigraphy is contraindicated, such as in pregnancy (the action). In Graves' disease, it characteristically shows a diffusely hypoechoic gland with markedly increased vascularity on color Doppler—a pattern often described as a 'thyroid inferno'. In contrast, thyroiditis typically appears hypovascular (the rationale) (16)."
Gold Standard (for Etiology):
"The definitive investigation to differentiate the functional causes of thyrotoxicosis is a Radioiodine Uptake and Scan (RAIU). It directly assesses the gland's iodine-trapping function (the rationale), clearly distinguishing between high-uptake states like Graves' or toxic nodules (which require anti-production therapy) and low-uptake states like thyroiditis (which require only symptomatic care). This distinction fundamentally alters the entire management plan (the action) (6)."
Monitoring & Staging
Antithyroid Drug Efficacy: "Serial fT4 levels are checked every 4-6 weeks after initiating ATDs to guide dose adjustments (the action). TSH is not a reliable marker in the early phase as it can remain suppressed for months due to prolonged feedback inhibition at the pituitary level, even after the patient becomes biochemically euthyroid (the rationale) (14)."
Safety Monitoring:
Full Blood Count (FBC): "An urgent differential white blood cell count is mandatory if a patient on ATDs develops fever or a sore throat. This is to immediately rule out agranulocytosis (a neutrophil count <0.5 x 10^9/L) (the rationale), which is a rare but potentially fatal complication that requires immediate cessation of the drug and hospital admission (the action) (16)."
Liver Function Tests (LFTs): "LFTs must be checked promptly if a patient develops jaundice, dark urine, pale stools, or significant pruritus. This is to screen for drug-induced hepatotoxicity (the rationale), another serious complication that requires immediate cessation of the offending drug (the action) (12)."
Management
Management goals are to rapidly control symptoms, restore a euthyroid state by reducing thyroid hormone production, and provide a long-term, definitive solution based on the underlying etiology and patient preference.
Management Principles
The management of hyperthyroidism focuses on rapid symptom control with beta-blockers, followed by a definitive treatment plan aimed at reducing thyroid hormone production. This plan should be developed through a process of shared decision-making, discussing the risks and benefits of the three main modalities—antithyroid drugs, radioactive iodine, and surgery—with the patient (12).
Acute Stabilisation (The First Hour)
While most patients do not require emergent stabilization outside of thyroid storm, rapid and effective symptom control is a key priority to alleviate distress.
Circulation/Symptom Control: "Administer a beta-blocker like Propranolol 20-40mg TDS to antagonize the peripheral adrenergic effects of excess thyroid hormone (the action). This provides rapid relief from debilitating symptoms like palpitations, tachycardia, and tremor while awaiting the slower onset of action of antithyroid drugs (the rationale) (14)." Propranolol is often preferred as it is non-selective and also weakly inhibits the peripheral conversion of T4 to the more potent T3. For patients with contraindications like severe asthma, a cardioselective beta-blocker or a calcium-channel blocker like diltiazem may be used (16).
Definitive Therapy
The choice between the three modalities depends on the etiology, patient factors, and a thorough discussion of risks and benefits.
First-Line Treatment (Antithyroid Drugs):
Carbimazole (or its active metabolite, Methimazole) is the first-line agent in Malaysia for Graves' disease and toxic nodular disease. A typical starting dose is 15-30mg daily. The medication is typically taken for 12-18 months for Graves' disease, after which an attempt to stop may be made if the patient is in remission (14, 16).
Propylthiouracil (PTU) is now reserved for specific situations due to a higher risk of severe hepatotoxicity: the first trimester of pregnancy (as carbimazole has a small risk of embryopathy) and in thyroid storm (as it also blocks peripheral T4-to-T3 conversion) (14).
Second-Line/Escalation (Definitive Cure):
Radioactive Iodine (RAI) Ablation: This is the preferred definitive therapy for patients with Graves' disease who relapse after ATDs and is a primary treatment for toxic nodular disease. It uses a single oral dose of I-131 to destroy hyperactive thyroid tissue. The intended and most common outcome is permanent hypothyroidism, which is considered a treatment success as it is easily and safely managed with lifelong levothyroxine replacement (12).
Surgery (Total or Near-Total Thyroidectomy): This provides the most rapid and certain definitive cure. It is the treatment of choice for patients with a very large goiter causing compressive symptoms, when there is a co-existing suspicious or malignant thyroid nodule, or in patients with severe, active ophthalmopathy (16). It is absolutely mandatory that patients are rendered biochemically euthyroid with ATDs before surgery to prevent precipitating a life-threatening intra-operative thyroid storm (2).
Supportive & Symptomatic Care
Beta-blockers: Continue as needed for symptom control, gradually tapering the dose as the patient becomes euthyroid.
Nutritional Support: Advise a healthy, calorie-dense diet to counteract the hypermetabolic state and promote weight regain.
Bone Health: Ensure adequate calcium and vitamin D intake. Consider a baseline bone density scan for postmenopausal women or patients with other risk factors for osteoporosis.
Eye Care for Graves' Orbitopathy: Simple measures like artificial tears for dry eyes, wearing sunglasses for photophobia, and sleeping with the head elevated can alleviate mild symptoms. Smoking cessation is the single most important intervention to prevent progression of eye disease.
Key Nursing & Monitoring Instructions
Monitor vital signs hourly in acutely unwell patients, paying close attention to temperature and heart rate, as these are key indicators of impending thyroid storm.
Strictly monitor for and report any new neurological signs, such as agitation, confusion, or decreased consciousness.
Educate the patient and their family on the critical importance of reporting the "red flag" symptoms for ATD side effects: fever, sore throat, mouth ulcers, jaundice, dark urine, or pale stools. This education must be documented.
Inform medical staff immediately if systolic BP drops below 90 mmHg, heart rate is persistently >110 bpm despite initial treatment, or if there is any sign of clinical deterioration.
When to Escalate
Knowing when to call for senior help is a critical safety net for any junior doctor. The threshold for escalation should be low.
Call Your Senior (MO/Specialist) if:
The patient meets criteria for thyroid storm (e.g., Burch-Wartofsky score >25, or any combination of fever, CNS dysfunction, and tachycardia).
The patient on an ATD calls with a fever and sore throat – they must be instructed to come to the hospital for an urgent FBC.
The patient presents with acute paralysis and a potassium level <3.0 mmol/L (suspected TPP).
The diagnosis remains uncertain after initial biochemical and etiological investigations.
The patient is pregnant, as this requires specialist multidisciplinary management.
Referral Criteria:
Refer to an Endocrinologist: For all new diagnoses of hyperthyroidism for confirmation of etiology and long-term management planning.
Refer to an Ophthalmologist: Urgently if there are any signs of severe or progressive Graves' Orbitopathy (e.g., visual loss, diplopia, corneal exposure).
Refer to a high-volume Thyroid Surgeon: If surgery is chosen as the definitive treatment modality, as surgeon experience significantly reduces the risk of complications like permanent hypoparathyroidism and recurrent laryngeal nerve injury.
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