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Hyperthyroidism

Definitions and Epidemiology

  • Hyperthyroidism: A clinical and biochemical syndrome caused by excessive production of thyroid hormones by the thyroid gland, characterized by increased circulating levels of T3 and T4 hormones and suppressed TSH levels. It has metabolic, cardiovascular, neurological, and systemic associated effects.
  • Thyrotoxicosis: A clinical and biological syndrome resulting from excess thyroid hormones at the tissue level, irrespective of their cause. It is defined by increased circulating levels of T3 and T4 along with TSH suppression, leading to significant metabolic, cardiovascular, neurological, and systemic effects.
Epidemiology
  • Prevalence: Affects 2-5% of women at some point in their lives.
  • Gender Ratio: 5:1 (female to male).
  • Age of Onset: Most frequently occurs between the ages of 20 and 40.
  • Causes: 99% of cases are due to intrinsic thyroid diseases; pituitary causes are extremely rare.

Causes of Hyperthyroidism

  • Common Causes:
      - Basedow-Graves Disease: An autoimmune disorder leading to thyroid hyperactivity.
      - Toxic Multinodular Goiter: A condition characterized by multiple nodules producing thyroid hormones.
      - Solitary Toxic Nodule: A single hormone-producing nodule.

  • Rare Causes:
      - Acute Thyroiditis (viral, autoimmune, post-radiation, postpartum).
      - Gestational and Neonatal Thyrotoxicosis: Excess thyroid hormone during pregnancy or shortly after birth.
      - Exogenous Iodine Administration: External sources of iodine leading to thyroid overactivity.
      - Medically Induced Causes: Such as treatment with amiodarone or immunotherapy.
      - TSH-Secreting Pituitary Tumors.
      - Metastatic Differentiated Thyroid Carcinoma.
      - HCG-Producing Tumors.
      - Hyperfunctioning Ovarian Teratoma (struma ovarii).

Basedow-Graves Disease

  • Definition: Thyroid hyperfunction with diffuse thyrotoxicosis of autoimmune origin, resulting from the production of anti-TSH receptor autoantibodies (TRAb) that have a stimulating effect. These autoantibodies induce increased thyrocyte function akin to TSH effects.
Clinical Manifestations
  • Patients may show one or more of the following:
      - Thyrotoxicosis
      - Ophthalmopathy (exophthalmia), characteristic of Basedow-Graves disease.
      - Goiter
      - Dermopatopathy (pretibial myxedema), which is rare.

Etiopathogenesis

  • Role of TRAb: Antibodies against the TSH receptor are pathognomonic for Graves' disease, which can stimulate thyroid hormone synthesis, secretion, cell proliferation, and iodine uptake.
  • TSH Receptor Antibodies: Some patients can have both TSH-blocking and stimulating antibodies that impact their clinical status depending on the ratio of these antibodies.
  • Anti-TPO Antibodies: There may also be an increase in anti-TPO antibodies related to the autoimmune aspect of the disease.
  • HLA Haplotypes: Graves' disease is associated with specific HLA haplotypes (e.g., HLA-B8, DR3, DR2).
Precipitating Factors
  • Excess Iodine: From contrast agents or medications; smoking; psychological stress; estrogens during the postpartum period; certain viral or bacterial infections can cause immune reactions resembling TSH, leading to production of TSH-binding antibodies.

Pathophysiological Mechanism of Thyrotoxicosis

  • Defective Immunoregulation: Suppressor T lymphocytes (Ts) fail to regulate helper T lymphocytes (Th), which encourages B lymphocytes to synthesize TRAb. TRAb (IgG) binds to the TSH receptors, stimulating thyroid hormone production similarly to TSH.
  • Hormone Levels: Increased free hormone levels (FT4 and FT3) are observed through both heightened production and decreased levels of thyroxine-binding globulin (TBG).
  • Effect on TSH: The hyperactivity of the gland suppresses TSH secretion.

Pathophysiological Mechanism of Graves' Ophthalmopathy

  • Immune Response: A local autoimmune reaction causes:
      - Cellular Immunity: Cytotoxic T lymphocytes release pro-inflammatory cytokines.
      - Humoral Immunity: Antibodies target antigens in fibroblasts and orbital muscles, with fibroblasts in the retroorbital area expressing heightened TSH receptors.
Consequences of the Autoimmune Reaction
  • Pathological Changes:
      - Inflammation and edema of retroorbital tissues from the accumulation of glycosaminoglycans (GAGs).
      - Connective tissue proliferation causes protrusion of eyeballs (exophthalmos), with lymphocytic infiltration of extraocular muscles leading to diplopia (double vision).

Classification of Graves' Ophthalmopathy (EUGOGO)

  • Easy form: Eyelid retraction < 2 mm; mild exophthalmos; no major disruption in daily life; absent or intermittent diplopia.
  • Moderate-Severe Form: Eyelid retraction ≥ 2 mm; moderate exophthalmos; constant diplopia; significant impact on quality of life.
  • Severe Form: Compressive optic neuropathy; severe corneal ulcers; decreased visual acuity, considered a medical emergency.

Severe Ophthalmopathy Effects

  • Complications: Severe forms result in persistent eyelid retraction, increasing the risk of photophobia, corneal ulcers, and optic nerve compression, potentially leading to blindness. Smoking and radioactive iodine therapy can exacerbate these conditions.

Graves Dermatopathy

  • Definition: An increase in serum levels of anti-TSH receptor antibodies (TRAb) stimulating fibroblasts, resulting in connective tissue accumulation at the pretibial region.
  • Clinical Appearance: The skin takes on a thickened, "orange peel" texture associated with thyrotoxic dermatopathy or pretibial myxedema.

Clinical Signs and Symptoms of Graves' Disease

  • General Symptoms:
      - Profuse sweating
      - Goiter and exophthalmos (eyelid retraction)
      - Heat intolerance
      - Palpitations and tachycardia
      - Weight loss despite increased or preserved appetite
      - Accelerated intestinal transit (diarrhea or vomiting)
      - Mental symptoms such as anxiety, irritability, insomnia, and memory issues.

Diagnostic Criteria for Hyperthyroidism

  • Hormonal Dosage:
      - TSH levels < 0.05 mU/L
      - High levels of free T3 (fT3) and free T4 (fT4)
      - High levels of TRAb, possibly high anti-TPO antibodies.
  • Imaging Studies:
      - Thyroid scintigraphy showing diffuse thyroid enlargement.
      - Ultrasound indicating hypoechoic areas with increased vascularity.
      - CT or MRI for evaluating retrobulbar muscle infiltration and edema.
  • Ophthalmic Examination: Assesses visual acuity, fundus, and intraocular pressure.

Differential Diagnosis

  • Graves' disease should be differentiated from other forms of hyperthyroidism, particularly in cases of significant weight loss, which might indicate:
      - Malabsorption syndromes
      - Tuberculosis (TB)
      - Gastritis
      - Gastroduodenal ulcer
      - Paraneoplastic syndromes.

Complications of Hyperthyroidism

  • Acute Complications:
      - Tachyarrhythmias or heart failure.
      - Thyrotoxic crisis ("thyroid storm"): A rare, life-threatening condition precipitated by stress or infections, leading to worsened hyperthyroidism symptoms, including hyperpyrexia, severe tachycardia, agitation, delirium, vomiting, and diarrhea.
  • Chronic Complications:
      - Osteoporosis
      - Cardiomyopathies.

Treatment of Hyperthyroidism

  • Medications:
      - Synthetic antithyroid drugs (e.g., Carbimazole, PTU - propylthiouracil, Tiamazole) alleviate thyrotoxicosis symptoms.
      - Beta-blockers (e.g., Propranolol) control symptoms from increased beta-adrenergic tone.
  • Radioiodine Therapy: Utilizing I131.
  • Surgical Intervention: Thyroidectomy as a definitive treatment option.

Hypothyroidism

Introduction to Hypothyroidism

  • Definition: Hypothyroidism is characterized by decreased thyroid hormone production. Thyroid hypofunction is primarily due to disorders of the thyroid gland but can also result from hypothalamic-pituitary dysfunction that reduces TSH action.

Classification of Hypothyroidism

  • Primary Thyroid Disease:
      - Acquired Causes:
        - Autoimmune: Conditions such as Hashimoto's thyroiditis, postpartum thyroiditis.
        - Iodine deficiency or medication-induced causes (e.g., Amiodarone, Lithium).
        - Infectious thyroiditis.
      - Congenital: Conditions like thyroid agenesis or ectopic thyroid formations (e.g., lingual thyroid).

  • Secondary Hypothyroidism (related to pituitary or hypothalamic dysfunction):
      - Isolated TSH deficiency or Hypopituitarism.
      - Post-surgical or post-radiation effects.
      - Peripheral resistance to thyroid hormones.

General Pathophysiological Mechanism in Hypothyroidism

  • Consequences of Hormone Deficiency:
      - A decrease in metabolism.
      - Accumulation of glycosaminoglycans (especially hyaluronic acid) in interstitial tissues.
      - Increased capillary permeability affecting proteins like albumin.

Mechanism of Hashimoto Thyroiditis

  1. Activation of self-reactive T helper lymphocytes against thyroid antigens.
  2. Antigen Presentation: Major Histocompatibility Complex (MHC) presents Thyroperoxidase (TPO) and Thyroglobulin (Tg), activating CD4+ Th1 lymphocytes that stimulate production of cytokines like TNF-α and IFN-γ.
  3. B-cell activation leading to antibody (anti-TPO) production.
  4. Destruction of thyroid parenchyma via:
       - Cell-mediated cytotoxicity by CD8+ lymphocytes.
       - Antibody-mediated cytotoxicity triggering complement activation, macrophages, and NK cells.
       - Chronic inflammation.
  5. Disturbance in negative feedback loops in hypothalamic-pituitary-thyroid axis.
  6. Initial State: High TSH with normal FT4 indicates subclinical hypothyroidism.
  7. Subsequent State: Elevated TSH with low FT4 signifies clinically overt hypothyroidism.

Clinical Signs and Symptoms of Hypothyroidism

Cardiovascular System
  • Reduced cardiac output due to lower heart rate and myocardial contraction.
  • Cardiomegaly related to interstitial edema.
  • ECG findings: microvoltage, prolonged PQ interval, AV blocks, and potential coronary artery disease associated with high cholesterol levels.
Respiratory System
  • Symptoms such as rhinitis, bronchial infections, and sleep apnea, partly due to macroglossia.
Digestive Symptoms
  • Common issues include constipation, hypotonic gallbladder, decreased gastric secretions, leading to slight weight gain from reduced metabolic activity and generalized edema.
Urogenital System
  • Gynecological symptoms include amenorrhea or oligomenorrhea.
  • Reduced glomerular filtration rate (GFR) leads to lower urine output and hyponatremia.
Central and Peripheral Nervous System
  • Cognitive impairments manifesting as mental slowness, lethargy, drowsiness, and loss of reflexes; severe cases may lead to syncope or coma.
Overview of Symptoms in Hypothyroidism
  • Cognitive Dysfunction: Includes fatigue, asthenia, and chilliness.
  • Digestive Issues: Constipation, decreased appetite, and weight gain.
  • Dermatological Effects: Dry skin, myxedema (non-pitting), periorbital edema, and hair loss.
  • Cardiovascular Changes: Bradycardia, diastolic hypertension, and fluid retention caused by heart failure.
  • Generalized Symptoms: Muscle weakness, anxiety, depression, and menstrual irregularities resulting in menometrorrhagia.

Diagnostic Criteria for Hypothyroidism

  • Hormonal Testing:
      - Low levels of fT3 and fT4.
      - Elevated TSH levels.
      - Positive anti-TPO antibodies indicate Hashimoto's thyroiditis.
  • Biochemical Abnormalities: Typical findings include hyponatremia, hypoglycemia, anemia, and elevated LDL cholesterol.
  • Ultrasound: Evaluates for nodules and their characteristics in the context of primary or secondary hypothyroidism.

Differential Diagnosis

  • Hypothyroidism in adults must be distinguished from:
      - Nephrotic syndrome and renal failure due to overlapping symptoms like edema.
      - Heart failure.
      - Depressive syndromes.
      - Acromegaly presenting initially with similar symptoms.
  • MRI of the sella and suprasellar regions aids in determining between primary and secondary/tertiary forms based on TSH levels.

Complications of Untreated Hypothyroidism

  • Progressive deterioration of metabolic functions if untreated.
  • Detected coronary artery disease necessitates coronary artery bypass grafting before initiating hormone replacement therapy due to the latter's potential to increase myocardial oxygen requirement and possibly exacerbate ischemic symptoms.

Treatment Approaches for Hypothyroidism

  • Thyroid Hormone Replacement Therapy: Standard treatment for both adults and children involves administering levothyroxine (LT4).
  • Monitoring Protocol: Dose adjustments occur at intervals of 4 to 6 weeks guided by TSH levels; replacement therapy efficacy monitored biannually through TSH and fT4 measurements.

Myxedematous Coma

Definition of Myxedematous Coma

  • A critical, severe complication of hypothyroidism, albeit rare. Predisposing factors include advanced age, trauma, or gastrointestinal bleeding.
  • Clinical Manifestations: Signs include severe myxedema that may evolve into symptoms like marked lethargy, hypothermia, extreme weakness, and coma. Bradycardia, heart failure, pericardial effusion, hypoglycemia, and hypoventilation may accompany this condition.
  • Laboratory Findings: Characteristic tests reveal significantly high TSH levels indicative of primary hypothyroidism, elevated serum cholesterol, hypoglycemia, and hyponatremia.

Pathogenesis of Myxedematous Coma

  • Triggered by reduced levels of T4 leading to dysfunctions in intracellular T3 metabolism affecting:
      - CNS Thermogenesis: Resulting in altered mental status and hypothermia.
      - Cardiovascular Stability: Impairments in fluid balance, inotropic and chronotropic responses, decreased cardiac output, and increased vascular permeability can cause shock.
      - Respiratory Function: Resulting in respiratory insufficiency and consequent cerebral anoxia, leading to coma.