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Causes of hypothyroidism symptoms and treatment Harrison textbook

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Hypothyroidism - Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Chapter 395 - Weetman, Mandel & Jameson

Causes of Hypothyroidism

Primary Hypothyroidism (TABLE 395-1)

Iodine deficiency remains the most common cause worldwide. In iodine-sufficient areas, the leading causes are autoimmune disease and iatrogenic factors.
Autoimmune (most common in iodine-sufficient regions):
  • Hashimoto's thyroiditis (goitrous form)
  • Atrophic thyroiditis (end-stage autoimmune destruction)
Iatrogenic:
  • Radioiodine (¹³¹I) treatment for hyperthyroidism
  • Subtotal or total thyroidectomy
  • External neck irradiation (for lymphoma or cancer)
Drugs:
  • Iodine excess (including iodine-containing contrast media)
  • Amiodarone
  • Lithium
  • Antithyroid drugs
  • p-aminosalicylic acid
  • Interferon-α and other cytokines
  • Aminoglutethimide
  • Tyrosine kinase inhibitors (e.g., sunitinib)
  • Immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab)
Congenital hypothyroidism (~1 in 2000-4000 newborns):
  • Thyroid dysgenesis (65%)
  • Inborn errors of thyroid hormone synthesis/dyshormonogenesis (30%)
  • TSH-R antibody-mediated (5%)
Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedel's thyroiditis
Other: Iodine deficiency, overexpression of type 3 deiodinase in infantile hemangioma and other tumors
Transient causes:
  • Silent thyroiditis (including postpartum thyroiditis)
  • Subacute thyroiditis
  • Withdrawal of thyroxine treatment in a euthyroid patient
  • After ¹³¹I treatment or subtotal thyroidectomy for Graves' disease
Central (Secondary/Tertiary) Hypothyroidism:
  • Pituitary or hypothalamic disease causing TSH or TRH deficiency

Pathogenesis of Autoimmune Hypothyroidism

The autoimmune process involves marked lymphocytic infiltration (CD8+ cytotoxic T cells predominate), local cytokine production (TNF, IL-1, IFN-γ), and complement-mediated cytotoxicity. TSH-receptor blocking antibodies are found in a minority. Genetic risk factors include HLA-DR3, DR4, DR5 and polymorphisms in PTPN22 and CTLA-4. Associated autoimmune conditions include type 1 diabetes, Addison's disease, pernicious anemia, and vitiligo. High iodine intake, low selenium, and early childhood hygiene ("hygiene hypothesis") increase risk.

Clinical Features / Symptoms (TABLE 395-3)

Onset is typically insidious - patients may not notice symptoms until euthyroidism is restored.
Skin and Appendages:
  • Dry skin, decreased sweating, thinning of epidermis
  • Nonpitting myxedema (due to glycosaminoglycan accumulation)
  • Puffy face with edematous eyelids, pretibial nonpitting edema
  • Pallor with yellow tinge (carotene accumulation)
  • Dry, brittle hair; diffuse alopecia; thinning of outer third of eyebrows
  • Retarded nail growth
Metabolic/GI:
  • Weight gain (modest, mainly fluid retention)
  • Constipation
  • Poor appetite
Cardiovascular:
  • Bradycardia, reduced stroke volume
  • Diastolic hypertension (increased peripheral resistance)
  • Pericardial effusion (up to 30% of patients)
  • Cool extremities (blood diverted from skin)
Neurological/Psychiatric:
  • Fatigue, lethargy, slow thinking
  • Depression, dementia (in severe/prolonged cases)
  • Cerebellar ataxia, peripheral neuropathy
  • Delayed deep tendon reflexes ("hung-up" reflexes)
  • Carpal tunnel syndrome
Respiratory:
  • Dyspnea (pleural effusion, impaired respiratory muscles, sleep apnea)
Reproductive:
  • Oligomenorrhea, amenorrhea, or menorrhagia (early stage)
  • Decreased libido, infertility, increased miscarriage risk
  • Elevated prolactin - may cause galactorrhea
Other:
  • Conductive or sensorineural deafness
  • Anemia (normocytic or macrocytic)
  • Elevated creatine phosphokinase, cholesterol, triglycerides
In children: slow growth, delayed facial/dental maturation, myopathy with muscle swelling, delayed puberty (or rarely precocious puberty).

Laboratory Evaluation

  • TSH is the best screening test; elevated TSH confirms primary hypothyroidism
  • Free T4 (FT4) confirms clinical hypothyroidism when TSH is elevated
  • Free T3 is normal in ~25% - not indicated for diagnosis
  • TPO and thyroglobulin (Tg) antibodies present in >95% of autoimmune hypothyroidism
  • Other findings: elevated CK, elevated cholesterol/triglycerides, normocytic or macrocytic anemia

Diagnostic Algorithm (Figure 395-2)

Evaluation of hypothyroidism - Harrison's Figure 395-2

Treatment

Clinical (Overt) Hypothyroidism

  • Standard replacement: Levothyroxine (LT4) 1.6 μg/kg body weight/day (typically 100-150 μg/day), taken at least 30 minutes before breakfast
  • After Graves' disease treatment, autonomous residual function often means lower doses needed (typically 75-125 μg/day)
  • Starting dose in adults under 60 without cardiac disease: 50-100 μg/day
  • Goal: TSH in the normal range, ideally the lower half of the reference range
  • Recheck TSH 6-8 weeks after starting or changing dose
  • Adjust in 12.5-25 μg increments (upward if TSH high; downward if TSH suppressed)
  • Clinical relief may take several months even after TSH normalizes
  • Once stable: annual TSH monitoring
Causes of increased LT4 requirements to consider:
  • Poor adherence (most common with TSH >normal on ≥200 μg/day)
  • Malabsorption (celiac disease, post-bowel surgery, H. pylori gastritis)
  • Oral estrogens or SERMs
  • Drug interactions reducing T4 absorption/metabolism: bile acid sequestrants, ferrous sulfate, calcium carbonate, proton pump inhibitors
Note on combination therapy: About 10-15% of patients have persistent symptoms despite normal TSH on LT4. Desiccated thyroid extract (USP) is not recommended (non-physiologic T3:T4 ratio). LT4 + liothyronine (T3) combination benefit has not been confirmed in prospective studies; T3 monotherapy is not appropriate long-term due to short half-life and fluctuating levels.

Subclinical Hypothyroidism

LT4 is recommended when:
  • TSH >10 mIU/L
  • Patient is pregnant or wishes to conceive
Annual monitoring is appropriate for most other patients. A treatment trial may be considered in young/middle-aged symptomatic patients or those with cardiovascular risk. Confirm TSH elevation is sustained over 3 months before treating. Starting dose: LT4 25-50 μg/day.

Special Populations

Elderly: Require ~20% less thyroxine. In elderly with coronary artery disease, start LT4 12.5-25 μg/day with increments every 2-3 months.
Pregnancy:
  • Confirm thyroid function immediately after pregnancy is confirmed
  • Monitor every 4 weeks during the first half of pregnancy; every 6-8 weeks after 20 weeks
  • Target TSH <2.5 mIU/L (lower half of trimester-specific range)
  • LT4 dose increases ~45% in athyroic women; less in Hashimoto's with residual function
  • As soon as pregnancy is confirmed: increase from once-daily to 9 doses per week
  • Return to pre-pregnancy dose after delivery
  • Separate LT4 from prenatal vitamins and iron supplements

Myxedema Coma

A severe, life-threatening emergency with 20-40% mortality despite treatment.
Triggers: sedatives, anesthetics, antidepressants, pneumonia, heart failure, MI, GI bleeding, stroke, sepsis, cold exposure
Treatment:
  • IV LT4: 200-400 μg bolus (loading dose), then 1.6 μg/kg/day IV (reduced 25% vs oral)
  • Consider adding IV or NG liothyronine: loading dose 5-20 μg, then 2.5-10 μg every 8 hours
  • IV hydrocortisone 50 mg every 6 hours (impaired adrenal reserve)
  • Ventilatory support; glucose/hypertonic saline if hyponatremia/hypoglycemia
  • Broad-spectrum antibiotics (pending exclusion of infection)
  • Passive rewarming only (active external warming only if temp <30°C - risk of cardiovascular collapse)
  • Avoid sedatives; reduce all medication doses (impaired drug metabolism)

Recent Evidence Note

A 2026 meta-analysis (PMID: 40579157) in J Clin Endocrinol Metab found that liothyronine-containing regimens are associated with reduced risk of dementia and mortality - this may eventually influence guidelines on combination therapy. A 2025 network meta-analysis (PMID: 39290156) reviewed patient treatment preferences. These are emerging data and do not yet supersede Harrison's recommendation that LT4 monotherapy remains the standard of care.
Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw Hill Medical), Chapter 395, pp. 3072-3075.
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