What are the typical signs, symptoms, diagnostic tests, and treatment recommendations for hypothyroidism?

Hypothyroidism: Clinical Presentation, Diagnosis, and Management

Clinical Signs and Symptoms

Hypothyroidism presents with nonspecific symptoms resulting from metabolic slowing, making early diagnosis challenging. 1, 2

Most Common Symptoms

• Fatigue and lethargy occur in 68-83% of patients, representing the cardinal manifestation of thyroid hormone deficiency 1, 3
• Weight gain affects 24-59% of patients due to decreased metabolic rate and reduced fat-burning capacity 1, 2
• Cold intolerance results from decreased heat production by the body 2, 4
• Cognitive impairment affects 45-48% of patients, manifesting as memory loss, difficulty concentrating, and slowed thinking 1, 3
• Menstrual irregularities occur in approximately 23% of women, including oligomenorrhea and menorrhagia 1, 3

Additional Clinical Features

• Constipation develops from slowed gastrointestinal motility 2, 4
• Dry skin (xeroderma) is a common dermatologic manifestation 2, 4
• Voice changes may occur in more advanced disease 4
• Depression is frequently reported 5, 3

Life-Threatening Presentation

• Myxedema coma represents severe decompensated hypothyroidism with hypothermia, hypotension, and altered mental status, carrying a mortality rate up to 30% and requiring intensive care unit management 1, 4

Diagnostic Testing

Diagnosis is based on biochemical testing, not clinical symptoms alone, as symptoms are nonspecific and overlap with many other conditions. 1, 2

Primary Diagnostic Tests

• TSH measurement is the first-line screening test with sensitivity above 98% and specificity greater than 92% 6, 1
• Overt primary hypothyroidism is defined as elevated TSH above the reference range (typically >4.5 mIU/L) with free T4 below the reference range 1, 5
• Subclinical hypothyroidism is defined as elevated TSH with normal free T4 levels 6, 5

Important Diagnostic Considerations

• Confirm elevated TSH with repeat testing after 3-6 weeks, as 30-60% of elevated TSH levels normalize spontaneously 6
• Measure both TSH and free T4 to distinguish between subclinical and overt hypothyroidism 6, 1
• The normal TSH reference range is 0.45-4.5 mIU/L, though this shifts upward with advancing age 6

Additional Testing

• Anti-thyroid peroxidase (anti-TPO) antibodies identify autoimmune etiology (Hashimoto's thyroiditis) and predict higher progression risk to overt hypothyroidism (4.3% per year vs 2.6% in antibody-negative individuals) 6
• Screening is NOT recommended for asymptomatic individuals in the general population 1, 4
• Targeted testing is recommended for high-risk patients including those with type 1 diabetes, first-degree relatives with hypothyroidism, pregnant women with autoimmune thyroid disease, and those on certain medications (immune checkpoint inhibitors, amiodarone, lithium) 1, 3

Treatment Recommendations

Levothyroxine monotherapy is the standard first-line treatment for hypothyroidism, being safe, inexpensive, and effective in normalizing thyroid function in the majority of patients. 1, 4, 5, 3

Treatment Initiation Based on TSH Levels

TSH >10 mIU/L with Normal Free T4

• Initiate levothyroxine therapy regardless of symptoms, as this threshold carries approximately 5% annual risk of progression to overt hypothyroidism 6
• Treatment may improve symptoms and lower LDL cholesterol, though evidence quality is rated as "fair" by expert panels 6

Overt Hypothyroidism (Elevated TSH with Low Free T4)

• Start levothyroxine immediately without delay to prevent cardiovascular dysfunction, adverse lipid profiles, and quality of life deterioration 6, 1

TSH 4.5-10 mIU/L with Normal Free T4 (Subclinical Hypothyroidism)

• Routine levothyroxine treatment is NOT recommended for asymptomatic patients, as randomized controlled trials found no improvement in symptoms 6, 4
• Consider treatment in specific situations: symptomatic patients, pregnant women or those planning pregnancy, patients with positive anti-TPO antibodies, or patients with goiter or infertility 6, 4

Levothyroxine Dosing Guidelines

Standard Adult Dosing

• For patients <70 years without cardiac disease, start at full replacement dose of 1.6 mcg/kg/day 6, 5
• For obese patients, use ideal body weight rather than actual body weight for dose calculation 6

Special Populations Requiring Lower Starting Doses

• For patients >70 years or with cardiac disease/multiple comorbidities, start at 25-50 mcg/day and titrate gradually 6, 1, 4
• For patients with known or suspected ischemic heart disease, start at 12.5-50 mcg/day to avoid unmasking cardiac ischemia or precipitating arrhythmias 4
• Rapid normalization of thyroid hormone can precipitate acute coronary syndrome, arrhythmias, or heart failure in cardiac patients 6

Critical Safety Consideration

• Before initiating or increasing levothyroxine, rule out concurrent adrenal insufficiency, as starting thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis 7, 6
• In patients with suspected central hypothyroidism or hypophysitis, always start physiologic dose steroids 1 week prior to thyroid hormone replacement 7, 6

Monitoring and Dose Adjustment

• Monitor TSH every 6-8 weeks while titrating hormone replacement until TSH reaches target range of 0.5-4.5 mIU/L 6, 1, 4
• Once adequately treated, repeat TSH testing every 6-12 months or if symptoms change 6, 1
• Adjust levothyroxine dose by 12.5-25 mcg increments based on TSH results, using smaller increments (12.5 mcg) for elderly or cardiac patients 6
• Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 6

Pregnancy-Specific Management

• Women with pre-existing hypothyroidism should increase their weekly levothyroxine dosage by 30% (take one extra dose twice per week) immediately upon pregnancy confirmation 4
• Target TSH <2.5 mIU/L in the first trimester 6
• Monitor TSH every 4 weeks until stable, then at minimum once per trimester 6
• Levothyroxine requirements typically increase by 25-50% during pregnancy 6

Common Pitfalls and Critical Warnings

Overtreatment Risks

• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, fractures, abnormal cardiac output, and ventricular hypertrophy 6, 1
• TSH suppression (<0.1 mIU/L) increases risk for atrial fibrillation 3-5 fold, especially in patients >60 years 6
• Prolonged TSH suppression causes accelerated bone loss and osteoporotic fractures, particularly in postmenopausal women 6
• If TSH <0.1 mIU/L develops on therapy, reduce levothyroxine dose by 25-50 mcg immediately 6

Undertreatment Risks

• Untreated or inadequately treated hypothyroidism increases risk of cardiovascular disease, heart failure, and increased mortality 1, 5, 3
• In pregnancy, untreated hypothyroidism increases risk of preeclampsia, low birth weight, miscarriage, and permanent neurodevelopmental deficits in the child 6
• Persistent hypothyroid symptoms adversely affect quality of life, cardiovascular function, and lipid metabolism 6

Diagnostic Pitfalls

• Do not treat based on a single elevated TSH value—30-60% normalize on repeat testing 6
• Never assume hypothyroidism is permanent without reassessment—consider transient thyroiditis, especially in recovery phase 6
• Avoid missing transient causes of TSH elevation: acute illness, recent iodine exposure, recovery from thyroiditis, or certain medications 6
• TSH can be transiently suppressed by acute illness, hospitalization, or medications—always confirm with repeat testing 6

Medication Administration

• Levothyroxine must be taken on an empty stomach, 30-60 minutes before breakfast, for optimal absorption 6
• Take levothyroxine at least 4 hours apart from iron, calcium supplements, or antacids 6

Consequences of Untreated Hypothyroidism

Cardiovascular Complications

• Hypothyroidism causes cardiac dysfunction including delayed relaxation, abnormal cardiac output, and increased systemic vascular resistance 6, 1
• Untreated hypothyroidism increases risk for heart failure and cardiovascular events 1, 2, 3
• Hypothyroidism causes hypertension and diastolic heart failure 6
• TSH >10 mIU/L is associated with hypertriglyceridemia and elevated LDL cholesterol 6

Reproductive Health

• Hypothyroidism causes disrupted ovulation, infertility, and increased risk of miscarriage 1, 3
• Menstrual irregularities including oligomenorrhea and menorrhagia are common 1

Metabolic Consequences

• Hypothyroidism causes insulin resistance and hyperglycemia in patients with diabetes 1
• Weight gain occurs due to decreased metabolic rate 1, 2

Severe Complications

• In infants, untreated hypothyroidism leads to mental retardation and delayed developmental milestones 2
• Myxedema coma is a life-threatening emergency with 30% mortality 1, 4