Hypothyroidism: A Clinical Review
Definition
Hypothyroidism is a clinical syndrome that arises when the thyroid gland fails to produce sufficient quantities of the thyroid hormones—primarily thyroxine (T4) and, to a lesser extent, triiodothyronine (T3)—to meet the body's physiological demands. T4 is the main secretory product of the thyroid gland and acts as a prohormone, which is converted in peripheral tissues to T3, the more biologically active hormone. This deficiency results in a generalised slowing of metabolic processes, affecting nearly every organ system (1). While the clinical presentation can be highly variable, the diagnosis is definitively confirmed through biochemical testing, with the hallmark finding in most cases being an elevated serum Thyroid-Stimulating Hormone (TSH) level, which represents the pituitary gland's robust response to a failing thyroid (2).
Epidemiology
In Malaysia, the precise prevalence of hypothyroidism varies in studies, with estimates ranging from 2.1% to as high as 10% in more comprehensive, nationwide research. This variation likely reflects differences in study design, such as the inclusion of undiagnosed subclinical cases, which represent a significant portion of the disease burden (3, 4). The prevalence of goitre (thyroid enlargement) in the Malaysian population is reported to be around 9.3% (3).
Gender Disparity: The condition demonstrates a striking predilection for women, who are affected far more often than men, with reported female-to-male ratios ranging from 6:1 to 10:1. This is strongly linked to the higher overall incidence of autoimmune diseases in females (3).
Age: The risk of developing hypothyroidism increases substantially with advancing age. While it can occur at any point in life, the highest incidence is observed in individuals between 45 and 55 years old (1).
Congenital Hypothyroidism (CH): A critical public health issue, the prevalence of CH in Malaysia is approximately 1 in 3,000 live births, a rate higher than that seen in some Western nations. A comprehensive national newborn screening programme, which tests for CH using cord blood TSH, has been successfully implemented since 2003 to enable early detection and prevent irreversible intellectual disability (5).
A Note on Pregnancy in Malaysia: The Malaysian Clinical Practice Guidelines (CPG) for thyroid disorders highlight a crucial local issue: the absence of published, population-specific, trimester-specific TSH reference ranges for pregnant Malaysian women. International guidelines recommend lower, more stringent TSH cut-offs during pregnancy due to physiological changes like hCG-mediated TSH receptor stimulation and increased thyroid hormone binding globulin. In the absence of local data, the CPG adopts a pragmatic and safe approach, recommending a single, universal TSH upper reference limit of 4.0 mIU/L throughout all trimesters of pregnancy (6).
Etiology
The causes of hypothyroidism are classified based on the anatomical level of the defect within the Hypothalamic-Pituitary-Thyroid (HPT) axis.
Primary Hypothyroidism (>99% of cases): The pathology resides within the thyroid gland itself, rendering it unable to produce hormones despite adequate or excessive stimulation (7).
Autoimmune (Hashimoto's Thyroiditis): This is the leading cause of spontaneous primary hypothyroidism in iodine-sufficient countries like Malaysia. It is an autoimmune condition with a known genetic predisposition linked to specific HLA types (1).
Iatrogenic (Treatment-Induced): This is an increasingly common cause.
Post-thyroidectomy (total or subtotal) for thyroid cancer or Graves' disease (1).
Post-radioactive iodine (RAI) therapy for hyperthyroidism, which leads to hypothyroidism in a significant number of patients, often within the first year, though the risk persists lifelong (1).
External beam radiation for head and neck cancers (e.g., lymphoma) can cause collateral damage to the thyroid gland (1).
Thyroiditis: Inflammation of the thyroid can lead to a triphasic course of hyperthyroidism, followed by transient (and sometimes permanent) hypothyroidism. This includes Postpartum Thyroiditis and Subacute (de Quervain's) Thyroiditis (6).
Drug-Induced: Several medications can impair thyroid function. Key examples include Amiodarone (which can induce hypothyroidism through its high iodine content via the Wolff-Chaikoff effect, or via a direct destructive thyroiditis) and Lithium (which inhibits thyroid hormone release). Other culprits include interferon-alpha and certain tyrosine kinase inhibitors used in oncology (1).
Iodine Imbalance: Both chronic iodine deficiency (rare in Malaysia due to salt iodization) and iodine excess (from supplements or contrast media) can disrupt hormone production (8).
Congenital Hypothyroidism: Defects present at birth, such as thyroid aplasia (absence), hypoplasia (underdevelopment), or dyshormonogenesis (enzyme defects in hormone synthesis) (1).
Central Hypothyroidism (<1% of cases): The thyroid gland is intrinsically normal but receives inadequate stimulation due to a problem in the pituitary or hypothalamus (9).
Secondary (Pituitary): Caused by conditions that damage the pituitary gland, such as pituitary adenomas (most common), pituitary surgery or radiation, postpartum pituitary necrosis (Sheehan's syndrome), or traumatic brain injury (8).
Tertiary (Hypothalamic): Less common, caused by tumours (e.g., craniopharyngioma), infiltrative diseases (sarcoidosis), or trauma affecting the hypothalamus (9).
Pathophysiology
Hypothyroidism results from a breakdown in the elegant negative feedback loop of the Hypothalamic-Pituitary-Thyroid (HPT) axis. In primary hypothyroidism, the thyroid gland's failure to produce T4 and T3 leads to a loss of negative feedback on the pituitary and hypothalamus. The pituitary responds by dramatically increasing its secretion of TSH in an attempt to stimulate the failing gland (9).
The most common cause, Hashimoto's thyroiditis, is a classic organ-specific autoimmune disease. The destruction of the gland is a gradual process driven by:
Cellular Immunity: This is the primary destructive mechanism. Autoreactive T-lymphocytes infiltrate the thyroid gland. Cytotoxic CD8+ T-cells directly kill thyroid follicular cells, while helper CD4+ T-cells orchestrate the inflammatory response. Histologically, this is seen as extensive lymphocytic infiltration, often with the formation of germinal centres and the presence of Hürthle cells (enlarged, eosinophilic follicular cells undergoing metaplastic change) (10).
Humoral Immunity: B-cells produce a variety of autoantibodies. The most clinically significant are anti-thyroid peroxidase (anti-TPO) antibodies, the serological hallmark of the disease, detected in over 90% of patients. These antibodies target a key enzyme involved in hormone synthesis (11).
The systemic effects of profound thyroid hormone deficiency are widespread:
Reduced Basal Metabolic Rate: This core defect leads to decreased energy expenditure and heat production, causing the classic symptoms of cold intolerance, fatigue, and modest weight gain (1).
Cardiovascular and Lipid Effects: Hypothyroidism directly impacts cardiovascular health by reducing myocardial contractility and heart rate (bradycardia). It also causes dyslipidemia, primarily by decreasing the number and activity of hepatic LDL receptors, leading to elevated total and LDL cholesterol and an increased risk of atherosclerosis (1).
Myxoedema: This hallmark finding is not simple oedema. It is caused by the accumulation of hydrophilic glycosaminoglycans (GAGs), like hyaluronic acid, in the interstitial space of tissues throughout the body. This GAG deposition draws in water, causing a characteristic non-pitting oedema, which is responsible for the puffy face (myxoedematous facies), coarse skin, hoarse voice (laryngeal oedema), and enlarged tongue (macroglossia) (2).
Clinical Presentation
The clinical presentation of hypothyroidism is notoriously variable and often subtle, with an insidious onset over months or years. The severity of symptoms correlates only moderately with the degree of biochemical abnormality (1).
Diagnostic Clues:
Woltman Sign: This is the delayed relaxation phase of deep tendon reflexes, most easily observed at the Achilles tendon. It is caused by slowed calcium reuptake by the sarcoplasmic reticulum in muscle. Its presence is highly specific, with one study reporting a positive predictive value of 92% (12).
Myxoedematous Facies: The classic appearance is highly characteristic: a dull, apathetic, and expressionless face, with significant periorbital puffiness, coarse and dry skin, thinning hair (especially the outer third of the eyebrows - madarosis), and often an enlarged tongue that may show teeth indentations (13).
Common Symptoms & Signs:
General: Fatigue, lethargy, sluggishness (most common), modest weight gain (typically 2-5 kg, mostly fluid), cold intolerance (highly specific) (1).
Dermatological: Dry, coarse, cool, and pale skin; coarse, brittle, thinning hair; brittle nails that grow slowly (8).
Neuromuscular: Proximal muscle weakness, myalgias (aches), cramps, and delayed deep tendon reflexes. Paresthesias in the hands from carpal tunnel syndrome are common (1).
Neuropsychiatric: Slowed thought processes ("brain fog"), impaired memory and concentration, depression, apathy, and in severe cases, psychosis ("myxoedema madness") (8).
Cardiovascular: Bradycardia, diastolic hypertension (due to increased systemic vascular resistance), distant heart sounds, and dyslipidemia (1).
Gastrointestinal: Constipation (highly specific), decreased appetite (1).
Reproductive: Menorrhagia or other menstrual irregularities; infertility or subfertility; galactorrhea (due to high TRH stimulating prolactin) (1).
Head & Neck: Hoarse, deep voice (due to vocal cord oedema); goitre (enlarged thyroid); macroglossia (enlarged tongue) (13).
⚠️ Red Flag Signs & Symptoms:
Myxoedema Coma This is a rare but life-threatening state of extreme hypothyroidism, a true endocrine emergency with a mortality rate of 20-60%. It is often precipitated by an event like infection, surgery, or cold exposure in a patient with long-standing, untreated hypothyroidism (14).
Altered Mental Status (Confusion, Lethargy, Stupor, Coma)
Severe Hypothermia (Core body temperature often <35°C)
Profound bradycardia and hypotension (shock)
Hypoventilation and respiratory failure (often requiring mechanical ventilation)
Complications
Cardiovascular: Dyslipidemia accelerates atherosclerosis, increasing the risk of coronary artery disease and myocardial infarction. Severe, long-standing hypothyroidism can lead to decreased cardiac output, heart failure, and pericardial effusions (1).
Neurological: In addition to carpal tunnel syndrome, severe cases can lead to profound cognitive impairment ("myxoedema madness") or coma (1, 8).
Myxoedema Coma: The most severe complication, representing a state of decompensated hypothyroidism leading to multi-organ failure and a high mortality rate (14).
Pregnancy: Untreated or undertreated maternal hypothyroidism is associated with significant risks for both mother (pre-eclampsia, placental abruption, postpartum hemorrhage) and fetus (preterm birth, low birth weight, and irreversible impairment of neurocognitive development, resulting in lower IQ) (3).
Prognosis
With appropriate lifelong levothyroxine replacement therapy and adherence, the prognosis for most patients with hypothyroidism is excellent, with a normal life expectancy and quality of life. However, some patients may report persistent symptoms like fatigue despite having a normalised TSH, a recognised clinical challenge. The prognosis for myxoedema coma remains poor, with mortality rates staying high even with aggressive treatment in an intensive care setting. Poor prognostic factors include advanced age, persistent hypothermia, and cardiovascular collapse (14).
Differential Diagnosis
Depression: This is a key differential due to the significant overlap in symptoms like fatigue, anhedonia, and cognitive slowing. However, depression is less likely to feature physical signs like bradycardia, a goitre, non-pitting oedema, or delayed reflexes. A normal TFT is crucial to distinguish the two.
Normal Ageing: In elderly patients, symptoms like fatigue, dry skin, constipation, and cognitive changes can be easily misattributed to the ageing process. A high index of suspicion and a screening TSH are necessary to avoid missing the diagnosis, especially as classic signs may be absent.
Chronic Fatigue Syndrome: Characterised by profound, disabling fatigue. The absence of other specific signs like cold intolerance, myxoedema, or abnormal TFTs helps distinguish it.
Anaemia: Can also present with fatigue, pallor, and lethargy. Anaemia is more associated with exertional dyspnoea and lacks features like cold intolerance or delayed reflexes. A full blood count will help differentiate, though it's important to remember that normocytic anaemia can be a feature of hypothyroidism itself.
Nephrotic Syndrome: Can present with significant oedema, but this oedema is pitting (due to severe hypoalbuminemia), whereas the oedema of hypothyroidism (myxoedema) is characteristically non-pitting.
Investigations
The Malaysian CPG recommends the practical approach of measuring both serum TSH and fT4 at the initial evaluation of a patient with suspected thyroid dysfunction, as this provides a complete biochemical picture from the outset (15).
Immediate & Bedside Tests
ECG: In a patient with suspected myxoedema coma or severe, long-standing hypothyroidism, an ECG is crucial to identify bradycardia, low voltage complexes, prolonged QT interval, or signs of ischaemia (the action), which are critical for immediate risk stratification and guiding resuscitation efforts (the rationale) (1).
Diagnostic Workup
First-Line Investigations (Thyroid Function Tests - TFTs):
High TSH, Low fT4: Confirms Overt Primary Hypothyroidism. This is the classic pattern unequivocally indicating that the thyroid gland has failed (9).
High TSH, Normal fT4: Defines Subclinical Hypothyroidism. This indicates the pituitary is working harder to maintain normal circulating hormone levels from a failing gland. It represents an early, mild stage of thyroid failure (2).
Low/Normal TSH, Low fT4: This pattern is a major red flag for Central Hypothyroidism. An inappropriately normal or low TSH in the face of low fT4 is profoundly abnormal. It is essential to urgently investigate for a pituitary or hypothalamic cause, such as a tumour (the action), as a healthy pituitary would have mounted a robust TSH response (the rationale) (9).
Gold Standard (Aetiology):
Anti-TPO Antibodies: Measurement of these antibodies is the key test to confirm Hashimoto's thyroiditis as the underlying autoimmune cause (the rationale). A positive result also helps in risk-stratifying patients with subclinical hypothyroidism, as it indicates a higher likelihood of progression to overt disease (the action) (6, 11).
Imaging:
Thyroid Ultrasound: This is not a routine investigation for the diagnosis of hypothyroidism. Its use is reserved for patients who have a palpable goitre or thyroid nodules on physical examination (the action) to assess for structural abnormalities, such as nodules that may require fine-needle aspiration biopsy to rule out malignancy (the rationale) (1). In Hashimoto's, an ultrasound may show characteristic findings such as diffuse hypoechogenicity and a heterogeneous parenchymal texture.
Monitoring of Therapy
TSH Monitoring: The primary goal of treatment is to normalise the TSH. After initiating or adjusting the levothyroxine dose, a repeat TSH should be performed in 6 to 8 weeks (the action). This specific timeframe is necessary to allow the entire HPT axis to re-equilibrate and reach a new hormonal steady state (the rationale). The Malaysian CPG recommends aiming for a TSH value in the lower half of the normal reference range (e.g., 0.5-2.5 mIU/L). Once the patient is on a stable dose, annual TSH monitoring is generally sufficient (6, 9).
Management
Management Principles
The management of hypothyroidism focuses on restoring a clinically and biochemically euthyroid state with lifelong levothyroxine replacement therapy. The goals are to resolve signs and symptoms, normalise serum TSH, and avoid overtreatment (iatrogenic thyrotoxicosis).
Acute Stabilisation (Myxoedema Coma Protocol)
This is a medical emergency requiring immediate ICU admission. Management should be initiated based on high clinical suspicion and must not be delayed for biochemical confirmation.
Airway/Breathing: Provide aggressive airway protection with a low threshold for intubation and mechanical ventilation (the action) to manage hypoventilation and prevent respiratory arrest, which can result from a combination of central respiratory drive depression, muscle weakness, and airway obstruction from macroglossia (the rationale) (14).
Circulation: Treat hypotension with cautious IV fluids and, if necessary, vasopressors (the action) to restore vital organ perfusion, which is severely compromised by profound bradycardia and decreased myocardial contractility (the rationale). Avoid rapid active rewarming (e.g., heating blankets), as this can cause peripheral vasodilation and precipitate cardiovascular collapse; passive rewarming with blankets is preferred (14).
Disability/Exposure:
Give Stress-Dose Steroids FIRST: Administer IV Hydrocortisone 100mg stat before giving any thyroid hormone. This is a critical, non-negotiable step to prevent precipitating a fatal adrenal crisis, as severe hypothyroidism can impair adrenal reserve, leading to a state of relative adrenal insufficiency (the rationale) (6).
IV Levothyroxine: Administer a loading dose of 200-400 mcg IV (the action) to rapidly replete the body's thyroid hormone stores, followed by a daily maintenance dose (the rationale). If IV formulation is unavailable, an oral loading dose via nasogastric tube is an alternative (6).
Treat the Precipitant: Aggressively search for and treat the underlying trigger, most commonly infection, with broad-spectrum antibiotics after obtaining appropriate cultures (the action), as failure to treat the precipitant is associated with very high mortality (the rationale) (14).
Definitive Therapy (Levothyroxine)
First-Line Treatment: Synthetic Levothyroxine (LT4) is the standard of care.
Dosing: In young, otherwise healthy adults, treatment can be initiated with a full replacement dose, typically calculated at 1.6 mcg/kg of ideal body weight per day. In the elderly or those with known or suspected coronary artery disease, treatment must be initiated with a low dose (e.g., 25-50 mcg daily) and titrated upwards very slowly every 4-6 weeks. This "start low, go slow" approach is crucial to avoid suddenly increasing myocardial oxygen demand, which could precipitate angina or a myocardial infarction (6).
Administration: Meticulous patient education on correct administration is critical for treatment success. The tablet must be taken on an empty stomach with only water, either at least 60 minutes before breakfast or at bedtime (at least three hours after the last meal). It must be separated by at least four hours from interfering substances like iron supplements, calcium carbonate, and certain antacids, which can form insoluble chelates with LT4 and impair its absorption (6).
Monitoring: Re-check TSH 6-8 weeks after initiation or any dose change. The goal is a TSH in the lower half of the normal range. Once stable, monitor annually. If the TSH remains high on an adequate dose, the clinician should suspect issues with adherence or malabsorption (e.g., celiac disease, H. pylori gastritis) (6, 9).
Management of Subclinical Hypothyroidism
Treat if TSH > 10 mIU/L: Treatment with LT4 is generally recommended for all patients in this category, as they are at a high risk of progressing to overt hypothyroidism and may be at increased risk for cardiovascular complications (16).
Consider Treatment if TSH 4.5-10 mIU/L: The decision to treat is individualized. Treatment should be strongly considered if the patient is symptomatic, pregnant or trying to conceive, has a goitre, has positive anti-TPO antibodies (indicating ongoing autoimmune destruction), or has established cardiovascular disease or multiple cardiovascular risk factors (16).
Supportive & Symptomatic Care
Constipation: Advise a high-fibre diet, adequate fluid intake, and increased physical activity. Stool softeners or osmotic laxatives may be required initially until the patient becomes euthyroid.
Myalgias/Arthralgias: Simple analgesics like paracetamol can be used for muscle and joint aches, which typically resolve with thyroid hormone replacement.
Dry Skin: Recommend the use of thick, unscented emollients and moisturisers, especially after bathing, to improve skin hydration and barrier function.
Nutritional Support: While weight gain is often modest and primarily due to fluid retention, referral to a dietitian can be helpful for patients struggling with weight management and to promote a heart-healthy diet, especially given the associated dyslipidemia.
Key Nursing & Monitoring Instructions
Strict monitoring of vital signs, fluid balance (input/output chart), and neurological status (GCS) in any patient admitted with severe hypothyroidism or myxoedema coma.
Monitor for clinical improvement (e.g., resolution of constipation, improved energy levels, warming of peripheries) as a sign of response to therapy.
Reinforce patient education on the critical importance of medication adherence and the specific rules for correct administration before discharge.
For inpatients with myxoedema, maintain a high index of suspicion for and monitor closely for signs of cardiac (e.g., new arrhythmias, signs of heart failure) or respiratory decompensation.
Long-Term Plan & Patient Education
Lifelong Therapy: It is essential to clearly communicate to the patient that hypothyroidism is almost always a permanent condition requiring lifelong hormone replacement.
Adherence: Stress the importance of taking levothyroxine daily without missing doses to maintain a stable euthyroid state and prevent the return of symptoms.
Signs of Over/Under-replacement: Educate the patient on the key symptoms of hyperthyroidism (palpitations, anxiety, tremor, heat intolerance, weight loss) and hypothyroidism (fatigue, cold intolerance, weight gain) and to report these to their doctor promptly.
Annual Follow-up: Advise a yearly clinical review and TSH check once on a stable dose to ensure the dose remains appropriate.
Intercurrent Illness: Instruct patients to continue taking their levothyroxine even when they are unwell with other illnesses.
When to Escalate
Call Your Senior (MO/Specialist) if:
You suspect Myxoedema Coma. This requires immediate senior input and urgent consultation with the intensive care team.
The patient is elderly with known ischaemic heart disease, and you are initiating levothyroxine, to ensure a safe titration plan.
The patient is pregnant and newly diagnosed with hypothyroidism, as this requires specialist management.
TFTs suggest Central Hypothyroidism (low/normal TSH with low fT4), as this requires urgent endocrinology consultation and neuro-imaging.
A patient has a persistently elevated TSH despite escalating doses of levothyroxine, suggesting a potential adherence or malabsorption issue that needs further investigation.
Referral Criteria:
Refer to an Endocrinologist for all cases of central hypothyroidism, difficult-to-manage or unstable primary hypothyroidism, hypothyroidism in pregnancy, or when considering treatment in complex subclinical cases.
Refer to a Cardiologist if a patient develops angina, arrhythmias, or worsening heart failure after starting levothyroxine.
Refer to a Gastroenterologist if a malabsorptive cause for treatment failure, such as celiac disease, is suspected.
References
Chaker, L., Bianco, A. C., Jonklaas, J., & Peeters, R. P. (2017). Hypothyroidism. The Lancet, 390(10101), 1550–1562.
Patil, N., Rehman, A., & Jialal, I. (2024). Hypothyroidism. In StatPearls. StatPearls Publishing.
Sri Kota Specialist Medical Centre. (n.d.). Hyperthyroidism and Hypothyroidism. Retrieved July 13, 2025, from https://www.srikotamedical.com/the-butterfly-in-me/
ClinicalTrials.gov. (2014). Thyroid Disorders in Malaysia: A Nationwide Multicentre Study. (Identifier: NCT02190214). Retrieved from https://clinicaltrials.gov/study/NCT02190214
Ministry of Health Malaysia. (2021). Consensus Guidelines for the Screening, Diagnosis and Management of Congenital Hypothyroidism. Putrajaya: MOH.
Ministry of Health Malaysia. (2020). Management of Thyroid Disorders - Quick Reference Guide. Putrajaya: MOH.
American Thyroid Association. (n.d.). Hypothyroidism. Retrieved July 13, 2025, from https://www.thyroid.org/hypothyroidism/
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (2021). Hypothyroidism (Underactive Thyroid). Retrieved July 13, 2025, from https://www.niddk.nih.gov/health-information/endocrine-diseases/hypothyroidism
Pirahanchi, Y., & Jialal, I. (2024). Physiology, Thyroid Stimulating Hormone. In StatPearls. StatPearls Publishing.
Mincer, D. L., & Jialal, I. (2024). Hashimoto Thyroiditis. In StatPearls. StatPearls Publishing.
Ragusa, F., Fallahi, P., Elia, G., Giamberardino, M. A., & Antonelli, A. (2019). Hashimotos' thyroiditis: From pathogenesis to treatment. Journal of Autoimmunity, 104, 102309.
Gujjar, A. R., & Kamalkishore, M. (2008). A classic sign of hypothyroidism: a video demonstration. CMAJ, 178(5), 565.
Johns Hopkins Medicine. (n.d.). Hypothyroidism. Retrieved July 13, 2025, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/hypothyroidism
Mathew, V., & Jialal, I. (2024). Myxedema Coma. In StatPearls. StatPearls Publishing.
Ministry of Health Malaysia. (2014). A Summary of the Consensus for the Management of Thyroid Disorders in Malaysia. Putrajaya: MOH.
Biondi, B., & Cooper, D. S. (2019). Subclinical Hypothyroidism. New England Journal of Medicine, 381(2), 179-180.
