Hypothyroidism

Hypothyroidism – High-Yield Study Guide for Medical Students

Definition

Hypothyroidism is a clinical state resulting from deficient production or action of thyroid hormones (T4 and T3), leading to a generalized slowing of metabolic processes. It is classified as:

• Primary hypothyroidism: impaired thyroid gland function (high TSH, low free T4).
• Secondary (central) hypothyroidism: pituitary failure (low or inappropriately normal TSH, low free T4).
• Tertiary hypothyroidism: hypothalamic dysfunction with TRH deficiency (rare in practice and often grouped with secondary).

Epidemiology

Hypothyroidism is one of the most common endocrine disorders and a high-yield topic for exams and clinical practice.

• Prevalence: Overt hypothyroidism affects about 0.2–2% of the general population; subclinical hypothyroidism is more common.
• Sex: Marked female predominance (up to 5–8:1 female-to-male ratio).
• Age: Incidence increases with age, especially in middle-aged and older adults.
• Geography: Autoimmune hypothyroidism (Hashimoto) is most common in iodine-sufficient regions; iodine deficiency is dominant in iodine-poor areas.
• Associated conditions: Common in patients with other autoimmune diseases (type 1 diabetes, celiac disease, pernicious anemia, vitiligo) and in those treated with neck irradiation or thyroid surgery.

Etiology and Pathophysiology

The pathophysiology of hypothyroidism centers on reduced circulating levels of T4 and T3, which decreases basal metabolic rate and affects virtually all organ systems.

Primary Hypothyroidism (Most Common)

• Chronic autoimmune thyroiditis (Hashimoto thyroiditis)
  • Cell- and antibody-mediated destruction of thyroid tissue.
  • Autoantibodies: anti–thyroid peroxidase (anti-TPO) and anti-thyroglobulin.
  • Initially may cause transient thyrotoxicosis ("Hashitoxicosis") followed by permanent hypothyroidism.
• Iatrogenic causes
  • Thyroidectomy or radioactive iodine therapy for Graves disease or thyroid cancer.
  • External neck radiation for lymphoma, head and neck cancers.
• Medications
  • Amiodarone (high iodine load, direct thyroid toxicity).
  • Lithium (inhibits thyroid hormone release).
  • Tyrosine kinase inhibitors, immune checkpoint inhibitors, interferon-α, and others.
• Iodine deficiency or excess
  • Deficiency leads to decreased hormone synthesis and goiter.
  • Excess iodine can trigger the Wolff–Chaikoff effect and reduce hormone synthesis, especially in underlying thyroid disease.
• Congenital hypothyroidism
  • Thyroid dysgenesis (agenesis, ectopy, hypoplasia) and dyshormonogenesis.
  • High yield for pediatrics: absent neonatal screening leads to severe intellectual disability (cretinism).
• Infiltrative diseases
  • Riedel thyroiditis, hemochromatosis, sarcoidosis, amyloidosis.

Secondary and Tertiary (Central) Hypothyroidism

• Pituitary causes (secondary)
  • Pituitary adenomas, surgery, radiation, Sheehan syndrome, infiltrative disorders.
  • Result in low or inappropriately normal TSH and low free T4.
• Hypothalamic causes (tertiary)
  • Mass lesions, infiltrative disease, radiation causing TRH deficiency.

Systemic Effects

Reduced thyroid hormone levels lead to decreased mitochondrial oxidative metabolism, impaired thermogenesis, and accumulation of glycosaminoglycans in interstitial tissues, producing:

• Bradycardia and reduced cardiac output.
• Constipation and slowed GI motility.
• Cold intolerance and weight gain (mostly from reduced metabolism and fluid retention).
• Myxedema (non-pitting edema) due to dermal mucopolysaccharide accumulation.
• Neuropsychiatric slowing, cognitive impairment, and depressed mood.

Clinical Presentation

Symptoms are often insidious and nonspecific, which is a classic exam point. Think of global slowing plus myxedematous changes.

General and Constitutional

• Fatigue, lethargy, low energy.
• Cold intolerance.
• Weight gain despite unchanged or decreased appetite.
• Decreased exercise tolerance.

Skin, Hair, and Nails

• Dry, coarse, cool skin.
• Hair thinning, coarse hair, loss of lateral third of eyebrows.
• Brittle nails.
• Non-pitting edema, classically periorbital (myxedema).

Cardiovascular

• Bradycardia, low-normal or diastolic hypertension.
• Decreased cardiac output, exertional dyspnea.
• Pericardial effusion in more severe, longstanding cases.

Gastrointestinal

• Constipation, reduced bowel frequency.
• Possible weight gain and bloating.
• Decreased appetite (may be present despite weight gain).

Neuromuscular

• Proximal muscle weakness and cramps.
• Delayed relaxation phase of deep tendon reflexes (classic exam sign).
• Paresthesias, carpal tunnel syndrome.

Neuropsychiatric

• Impaired concentration and memory.
• Depressed mood, apathy.
• In severe cases, psychosis ("myxedema madness").

Reproductive and Endocrine

• Menorrhagia, oligomenorrhea, or secondary amenorrhea.
• Subfertility or infertility.
• Hyperprolactinemia due to elevated TRH stimulating prolactin.

Metabolic and Hematologic

• Hyperlipidemia, especially elevated LDL and triglycerides.
• Hyponatremia due to impaired free water clearance and increased ADH.
• Normocytic or macrocytic anemia.

Special Scenarios

• Subclinical hypothyroidism: Often asymptomatic; may have subtle fatigue and weight gain with elevated TSH and normal free T4.
• Congenital hypothyroidism: Prolonged neonatal jaundice, hypotonia, macroglossia, umbilical hernia, poor feeding; untreated leads to neurocognitive impairment and short stature.
• Myxedema coma: Life-threatening decompensated severe hypothyroidism with hypothermia, bradycardia, hypotension, hypoventilation, altered mental status, and precipitating stressor (infection, MI, trauma, sedative use).

Diagnosis

Diagnosis relies primarily on thyroid function tests, interpreted in clinical context. Always consider whether you are dealing with primary or central disease.

Initial Laboratory Evaluation

• Serum TSH
  • Most sensitive screening test for primary hypothyroidism.
  • Elevated TSH with low free T4 confirms primary hypothyroidism.
• Free T4 (FT4)
  • Low FT4 with high TSH: overt primary hypothyroidism.
  • Normal FT4 with high TSH: subclinical hypothyroidism.
  • Low FT4 with low or inappropriately normal TSH: central hypothyroidism.

Autoimmune Markers

• Anti-thyroid peroxidase (anti-TPO) antibodies
  • Most sensitive marker for Hashimoto thyroiditis.
  • Positive in the majority of autoimmune hypothyroidism.
• Anti-thyroglobulin antibodies
  • Supportive but less sensitive than anti-TPO.

Additional Tests When Indicated

• Thyroid ultrasound
  • Not routinely required for hypothyroidism alone.
  • Useful if there is goiter, nodularity, or suspicion for malignancy.
• Pituitary imaging (MRI)
  • Indicated when central hypothyroidism is suspected or there are other pituitary hormone deficiencies.
• Additional pituitary hormones
  • Check cortisol, gonadotropins, prolactin, IGF-1 when central disease is suspected.

Interpretation Patterns (High-Yield)

• Primary overt hypothyroidism: TSH > upper limit, free T4 low.
• Primary subclinical hypothyroidism: TSH mildly elevated, free T4 normal.
• Central hypothyroidism: free T4 low, TSH low or inappropriately normal.
• Euthyroid sick syndrome (non-thyroidal illness): low T3, normal or low T4, variable TSH; clinical context of acute illness is key.

Management

The cornerstone of therapy is thyroid hormone replacement, almost always with levothyroxine (synthetic T4). Treatment goals are symptom resolution and normalization of TSH (or FT4 in central disease).

Levothyroxine Therapy

• Drug of choice: Levothyroxine (L-thyroxine, synthetic T4).
• Dosing in healthy, non-pregnant adults < 60 years without cardiac disease
  • Typical full replacement dose: ~1.6 mcg/kg/day based on ideal body weight.
  • Can start at or near full dose in young, otherwise healthy patients.
• Elderly or patients with known coronary artery disease
  • Start low (e.g., 12.5–25 mcg/day) and titrate slowly every 6–8 weeks to avoid precipitating angina, arrhythmias, or MI.
• Administration
  • Take on an empty stomach, typically in the morning 30–60 minutes before breakfast.
  • Alternatively, at bedtime ≥ 3–4 hours after last meal, but be consistent.
• Interacting substances that reduce absorption
  • Iron supplements, calcium carbonate, aluminum hydroxide antacids, cholestyramine, sucralfate, proton pump inhibitors, some fiber supplements.
  • Separate these by at least 4 hours from levothyroxine dosing.

Monitoring and Dose Adjustment

• Primary hypothyroidism
  • Check TSH (and FT4 if needed) 6–8 weeks after any dose change.
  • Target TSH generally in the reference range (about 0.5–4.0 mIU/L), individualized to patient and lab.
  • Once stable, monitor TSH every 6–12 months or if clinical status changes.
• Central hypothyroidism
  • TSH is unreliable; titrate levothyroxine to maintain FT4 in the upper half of the reference range.

Special Populations

• Pregnancy
  • Increased thyroxine requirements due to increased TBG and volume of distribution.
  • Women on levothyroxine often need a 25–30% dose increase as soon as pregnancy is confirmed.
  • Trimester-specific TSH targets are lower than the non-pregnant range; monitor TSH and FT4 every 4 weeks in early pregnancy.
  • Untreated or undertreated hypothyroidism is associated with miscarriage, preeclampsia, anemia, and impaired fetal neurodevelopment.
• Subclinical hypothyroidism
  • Treatment is individualized.
  • Generally treat if TSH ≥ 10 mIU/L, positive anti-TPO, symptomatic, pregnant, or planning pregnancy.
  • For mild TSH elevation (e.g., 4.5–9.9 mIU/L), consider treatment in symptomatic patients or those at higher cardiovascular risk.
• Myxedema coma
  • Endocrine emergency requiring ICU-level care, IV levothyroxine (with or without liothyronine in some protocols), stress-dose glucocorticoids, and supportive measures.
• Congenital hypothyroidism
  • Initiate levothyroxine as soon as possible, ideally within the first 2 weeks of life, to optimize neurocognitive outcomes.
  • Dose is higher per kg than adults; frequent monitoring is required.

Complications and Prognosis

With timely diagnosis and adequate treatment, prognosis is excellent for most patients.

• Cardiovascular
  • Elevated LDL and triglycerides, increased atherosclerotic risk if untreated.
  • Pericardial effusion, reduced cardiac output, heart failure in severe cases.
• Metabolic and hematologic
  • Hyperlipidemia, weight gain, hyponatremia.
  • Anemia (normocytic or macrocytic), rarely contributing to fatigue.
• Reproductive
  • Infertility, menstrual irregularities, increased miscarriage risk.
  • Adverse obstetric outcomes if inadequately treated in pregnancy.
• Neurologic and cognitive
  • Cognitive impairment, depression, peripheral neuropathy.
  • In congenital hypothyroidism, permanent intellectual disability if therapy is delayed.
• Myxedema coma
  • High mortality despite aggressive treatment; prevention is key through early recognition and adequate dosing.

Key Clinical Pearls for Exams and Practice

• TSH is the primary screening and monitoring test for primary hypothyroidism; always pair with FT4 when establishing the diagnosis or when findings are discordant.
• Differentiate primary from central hypothyroidism: high TSH with low FT4 indicates primary; low or inappropriately normal TSH with low FT4 suggests central disease and mandates evaluation of the pituitary–hypothalamic axis.
• Hashimoto thyroiditis is the most common cause of hypothyroidism in iodine-sufficient areas; think of positive anti-TPO antibodies and goiter with a firm, rubbery thyroid.
• Subclinical hypothyroidism is common. Treatment is generally recommended for TSH ≥ 10 mIU/L or in symptomatic, pregnant, or high-risk patients with milder elevations.
• Levothyroxine should be taken on an empty stomach and separated from calcium, iron, and other interfering medications to ensure consistent absorption.
• In elderly patients and those with CAD, always start at a low levothyroxine dose and titrate slowly to avoid precipitating ischemia or arrhythmias.
• In pregnancy, levothyroxine requirements increase; counsel patients to contact their clinician early in pregnancy for dose adjustment and close monitoring.
• Delayed relaxation of deep tendon reflexes and non-pitting periorbital edema (myxedema) are classic physical exam findings that show up in exams.
• Myxedema coma is a decompensated form of severe hypothyroidism with high mortality. Look for hypothermia, bradycardia, hypotension, and altered mental status in a patient with known or suspected hypothyroidism exposed to a precipitating stressor.
• Always check adrenal function (or empirically give stress-dose glucocorticoids) in suspected central hypothyroidism or myxedema coma before or along with initiation of thyroid hormone to avoid precipitating adrenal crisis.

Quick Exam-Oriented Summary

• Most common cause: Hashimoto thyroiditis in iodine-sufficient regions; iodine deficiency globally.
• Best initial test: TSH (with FT4 to confirm and classify).
• Classic labs in primary hypothyroidism: ↑ TSH, ↓ FT4; subclinical: ↑ TSH, normal FT4.
• Treatment: Levothyroxine, dose tailored to body weight, age, cardiac status, and pregnancy.
• Monitoring: TSH every 6–8 weeks after dose changes; once stable, 6–12 monthly checks.