Medical Pharmacology Chapter 30:  Thyroid and Antithyroid Drugs

• Overview:  hypothyroidism

  1. Cause: inadequate thyroid hormone synthesis

  2. Cretinism -- when hypothyroidism is present from birth and accompanied by developmental abnormalities

  3. Myxedema: severe hypothyroidism associated with:

     • Deposition of hydrophilic mucopolysaccharides in the dermis (ground substance) and other tissues-- causing:

       • Facial feature thickening

       • Doughy skin induration

• Pretibia myxedema

  • Adult hypothyroidism: Pretibial myxedema in the foot and lower extremity skin © 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

• Hypothyroidism: pathogenesis

  1. Inadequate thyroid hormone synthesis causes TSH hypersecretion which results in goiter

  2. If this compensatory physiological response is insufficient, goitrous hypothyroidism occurs

  • Causes of goitrous hypothyroidism (North America)

    • Most common cause: Hashimoto's disease 

      • Mechanism:

        1. Defective binding of iodide

        2. Abnormal secretion of iodoproteins

    • Iodide-induced goiter with or without hypothyroidism: intrinsic defect inorganic binding mechanism

      • Euthyroid patients with Graves' disease (particularly following surgery or radioiodine therapy), patients with Hashimoto's disease, and normal fetuses are particularly susceptible to iodide-induced goiter.

      •  

        Hashimoto thyroiditis

        (Right) Struma lymphomatosa in Hashimoto thyroiditis, gross. Note: diffuse, pale yellow infiltrate affecting the entire thyroid. The yellow infiltrate is caused by an influx of lymphocytes, which may form follicles. Normal thyroid (Left) KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

• Hypothyroidism: Clinical presentation

  • Neonates (note that cretinism may be present at birth, but usually is apparent within the first few months after birth as a function of the extent of thyroid failure)

    • Manifestations include:

      • Physiologic jaundice

      • Constipation

      • Somnolence

      • Feeding problems

    • Since early clinical diagnosis may be difficult and early treatment is necessary to ensure normal intellectual development,all neonates should be screened for hypothyroidism by measuring serum T₄ or TSH.

      • Congenital Hypothyroidism in a 3 Month-old Infant

        Rastogi and LaFranchi; licensee BioMed Central Ltd.  "3 month old infant with untreated CH (Congential Hypothyroidism), showing myxedematous facies, macroglassia, and skin mottling." original source:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903524/figure/F1/ http://www.en.wikipedia.org/wiki/File:CDpic1.png

  • Young Children

    • Coarse features, protruding tongue, broad, flat nose, widely set eyes, dry skin, coarse hair. impaired mental development, retarded bone age, epiphyseal dysgenesis, delayed dentition.

  • Older Child

    • Retardation of linear growth, delayed puberty.

    • Poor school performance.

  • Adult

    • Fatigue, lethargy, constipation, cold intolerance

    • Slowing of intellectual and motor activity.

    • Lessened appetite; increased weight.

    • Dry skin; dry hair (may fall out).

    • Deeper, hoarser voice.

    • With Advanced Disease: (florid myxedema).

      • Dull, expressionless facies, sparse hair, periorbital puffiness , large tongue, rough and doughy skin (cool, pale).

        • Fred HL van Dijk HA "Someone with myxedema showing an expressionless face, periorbital puffiness, pallor." (1/26/2014) http://www.en.wikipedia.org/wiki/File:Myxedema_face.png

      • Enlarged heart (dilation, pericardial effusion).

      • Adynamic ileus.

      • Without treatment: myxedema coma possible with respiratory depression and increased P_CO2 .

  • Laboratory Tests

    • Single most useful: serum TSH

      • Increased levels in thyroprivic and goitrous.

      • Normal or undetectable in pituitary or hypothalamic hypothyroidism.

        • In hypothalamic hypothyroidism: TSH hypersecretion is associated with hypersecretion of other pituitary hormones.

    • All hypothyroidism:

      • Decreased serum T₄ and free T₄I.

      • Serum T₃ may be decreased  less than serum serum T₄ .

    • Some other abnormal laboratory results:

      • Increase serum cholesterol (hypothyroidism of thyroid origin).

      • Increased creatinine phosphokinase.

      • Increased aspartate transaminase.

      • Indications of pernicious anemia.

• Pharmacological treatment

  • Synthetic hormones

    • Levothyroxine, preferred.

    • Liothyronine.

    • Liotrix (combination of new L-thyroxine and liothyronine).

  • Neonatal, infantile, and juvenile hypothyroidism: early full replacement therapy vital to improve likelihood of:

    • Normal intellectual development.

    • Normal growth.

  • If neonatal, infantile, and juvenile presentations result from pituitary and hypothalamic hypothyroidism, treatment with hydrocortisone should precede thyroid replacement therapy:

    • Rationale:acute adrenocortical insufficiency may because by the increase in metabolic rate with increase glucocorticoid clearance following thyroid hormonal treatment.

  • Adults:

    • Rapid treatment desirable especially in patients with:

      1.  Myxedema coma.

      2.  Hypothyroid patients needing to undergo emergency surgery (these patients have extreme sensitivity to CNS depressants).

         • IV levothyroxine with hydrocortisone may be appropriate.

    • To patients with myxedema coma and systemic illness may have reduced ability to convert T₄ to T₃. In these cases supplemental liothyronine may be added to levothyroxine.

*- Thyroprivic: refering to lack of thyroidhormone (e.g. removal of the gland or suppression of glandular function).

Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633.

Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2012-2034