What are the clinical features, diagnostic criteria, and management of primary hypothyroidism?

Hypothyroidism: Clinical Features and Management

Clinical Presentation

Hypothyroidism presents with a constellation of symptoms reflecting metabolic slowing across multiple organ systems, with fatigue (68-83%), weight gain (24-59%), cognitive impairment (45-48%), and menstrual irregularities (23%) being the most common manifestations. 1

Cardinal Symptoms

• Severe, unrelenting fatigue that interferes with daily activities is the hallmark symptom 2
• Unexplained weight gain of 5-10 pounds or more without increased caloric intake 2
• Cold intolerance due to decreased heat production from reduced metabolic rate 3
• Constipation resulting from slowed gastrointestinal motility 4, 3
• Dry skin (xeroderma) and extensive hair loss 2, 3, 5
• Cognitive dysfunction including memory loss, difficulty concentrating, and "brain fog" 2, 1
• Menstrual irregularities such as oligomenorrhea and menorrhagia 1

Cardiovascular Manifestations

• Cardiac dysfunction including delayed relaxation, abnormal cardiac output, and diastolic heart failure 2
• Hypertension with characteristic delayed ankle reflexes 2
• Increased cardiovascular event risk including heart failure 1

Metabolic and Endocrine Effects

• Insulin resistance and hyperglycemia in patients with diabetes 1
• Disrupted ovulation, infertility, and increased miscarriage risk 1
• Elevated LDL cholesterol 2

Diagnostic Criteria

Primary Hypothyroidism (Most Common)

Measure TSH and free T4 simultaneously—elevated TSH (>4.5 mIU/L) with low free T4 confirms overt primary hypothyroidism. 2, 1, 5

• TSH has sensitivity >98% and specificity >92% for detecting thyroid dysfunction 2
• Overt hypothyroidism: TSH elevated AND free T4 below reference range 1, 6
• Subclinical hypothyroidism: TSH elevated (typically >4.5 mIU/L) with normal free T4 and T3 6, 7

Secondary (Central) Hypothyroidism (Rare)

Low or inappropriately normal TSH with low free T4 indicates pituitary or hypothalamic dysfunction. 4, 5

• Often accompanied by other pituitary hormone deficiencies 4
• May present with headache and visual field changes suggesting pituitary mass effect 4
• Always evaluate other pituitary hormones, especially the hypothalamic-pituitary-adrenal axis 4, 6

Confirmation Testing

• Repeat TSH after 3-6 weeks before initiating treatment, as 30-60% of elevated TSH levels normalize spontaneously 2
• Measure anti-TPO antibodies to identify autoimmune etiology (Hashimoto thyroiditis), which predicts 4.3% annual progression to overt hypothyroidism versus 2.6% in antibody-negative individuals 2

Etiology

Primary Causes

• Hashimoto thyroiditis (autoimmune disease) causes up to 85% of primary hypothyroidism in iodine-replete areas 1, 5
• Iodine deficiency in areas with inadequate nutritional iodine 1, 7
• Radioiodine therapy or thyroid surgery 3, 5
• Medications: immune checkpoint inhibitors (6-20% incidence), amiodarone 2, 1
• Radiation therapy to the neck 3

Risk Factors

• First-degree relative with hypothyroidism (genetic factors) 1
• Female sex and older age 3, 1
• Pregnancy in the setting of underlying autoimmune thyroid disease 1

Management

Treatment Thresholds

Initiate levothyroxine immediately for:

• TSH >10 mIU/L regardless of symptoms (5% annual progression risk to overt hypothyroidism) 2, 6
• Any TSH elevation with low free T4 (overt hypothyroidism) 2, 1
• Symptomatic patients with any degree of TSH elevation 2
• Pregnant women or those planning pregnancy with any TSH elevation 2, 6

Consider treatment for TSH 4.5-10 mIU/L with normal free T4 in:

• Symptomatic patients 2
• Positive anti-TPO antibodies 2, 6
• Infertility or goiter 2, 6

Levothyroxine Dosing

For patients <70 years without cardiac disease:

• Start with full replacement dose of 1.6 mcg/kg/day 2
• Monitor TSH every 6-8 weeks during titration 2

For patients >70 years or with cardiac disease:

• Start with low dose of 25-50 mcg/day and titrate gradually 2, 6
• Rapid normalization can unmask or worsen cardiac ischemia 2

Target TSH: 0.5-4.5 mIU/L with normal free T4 2, 6

Critical Safety Considerations

In central hypothyroidism or suspected adrenal insufficiency:

• Always replace cortisol BEFORE thyroid hormone to prevent life-threatening adrenal crisis 2, 4, 6
• Start hydrocortisone at least 1 week prior to levothyroxine 2, 4

Monitoring

• TSH and free T4 every 6-8 weeks while titrating dose 2
• Once stable, monitor TSH annually or sooner if symptoms change 2
• Adjust dose by 12.5-25 mcg increments based on TSH response 2

Complications of Untreated Hypothyroidism

• Myxedema coma: hypothermia, hypotension, altered mental status with 30% mortality 1
• Heart failure and cardiovascular events 3, 1
• Mental retardation and delayed milestones in infants 3
• Infertility and pregnancy complications 1

Overtreatment Risks

Approximately 25% of patients on levothyroxine are unintentionally overtreated (TSH <0.1 mIU/L), increasing risks for: 2

• Atrial fibrillation (3-5 fold increased risk) 2
• Osteoporosis and fractures especially in postmenopausal women 2
• Cardiovascular mortality 2