Thanks to Dr. Ronald M. Goldenberg, MD, FRCPC, FACE, Staff Endocrinologist, North York General Hospital, ON Canada; Endocrinologist & Medical Co-Director, LMC Endocrinology Centres, Toronto, ON Canada, and Dr. William Semchuk, M.Sc., Pharm.D., FCSHP., Manager, Clinical Pharmacy Services, Regina Qu’Appelle Health Region 14, Regina, SK Canada for their expertise with the initial review of this topic.


A clinical state defined as decreased production of thyroid hormone, by the thyroid gland resulting in deficiency of circulating hormone which regulates essential functions; such as heart rate, digestion, physical growth, and if left untreated, leads to multiple organs and tissues damage.

Thyroid hormone resistance: Mutation within thyroid hormone receptors (TRB) leads to poor hormone recognition by tissues and causes a condition similar to low thyroid production state.


Primary hypothyroidism:

  • Indicates decreased thyroidal secretion of thyroid hormone by factors affecting the thyroid gland itself

Secondary hypothyroidism:

  • Decreased thyroidal secretion of thyroid hormone can also be caused by insufficient stimulation of the thyroid gland by thyroid-stimulating hormone (TSH), due to factors directly interfering with pituitary TSH release.

Tertiary hypothyroidism:

  • Indicates decreased thyroidal secretions due to indirect reduction in thyroid releasing hormone (TRH) released from the hypothalamus.

Note: Clinically it is difficult to differentiate between the secondary and tertiary hypothyroidism so they are often collectively referred to as “central hypothyroidism”

Myxedema coma:

A severe state of hypothyroidism which, if left untreated, leads to severe stress and infections.

  • Myxedema coma is a potentially lethal but rare condition, occurring with severe hypothyroidism


Various functional or structural disorders are involved which may cause hypothyroidism, and are categorized as follows:

Primary hypothyroidism:

  • Deficient thyroid hormone production by thyroid gland. Usually inherited. Accounts for approximately 90-95% of hypothyroidism

Central hypothyroidism:

  • Inadequate stimulation of the normal gland from defect at the level of pituitary or hypothalamus

Peripheral (extrathyroidal) hypothyroidism:

  • Symptoms exhibiting hypothyroid state, despite normal structure and function of the thyroid gland and due to peripheral tissue resistance to thyroid hormone

Causes of Hypothyroidism



  • Predominant age: >40 years
  • Predominant gender: Female > Male, 5:1-10:1


  • 5-10/1,000 in general population
  • Common in elderly
  • >65 years of age, increases to
    • 6-10% of women
    • 2-3% of men

Hashimoto’s thyroiditis:

  • Annual incidence
    • Women: 400 per 100,000
    • Men: 100 per 100,000
  • Mean age at diagnosis: 60 years
  • Commonest cause of hypothyroidism


  • Hypothyroidism results from dysfunction in the normal homeostasis in the formation and regulation of the active form of thyroid hormone T3
  • Thyroid hormone deficiency may stem from a variety of causes including destruction/atrophy of the thyroid gland (primary hypothyroidism), pituitary insufficiency (secondary hypothyroidism) or from abnormalities of the hypothalamic-pituitary axis (tertiary hypothyroidism)


Normal Regulation Hypothyroidism-Pathophisiology-Hypothyroid

In primary hypothyroidism, in response to a drop in T4 secretion from the thyroid gland, TSH secretion from the pituitary is increased. Thus, an elevated TSH is the primary marker of primary hypothyroidism.

Clinical Presentation

Clinically the disease varies from one patient to the other depending upon cause, duration, and severity of the hypothyroid state. Since thyroid hormones influence most organs, tissues, and cells of the body, there can be a wide spectrum of sign and symptoms in this disorder (see figure).


Symptoms-Clinical features-Hypothyroid


Note: An endocrinologist would most likely recognize the subtle manifestations and would be more skilled to do physical thyroid gland examination. Consultation is recommended for:

  • Patients of age ≤18 years
  • Patients who do not respond to treatment
  • Pregnant patients
  • Cardiac patients
  • Structural changes in the thyroid gland
  • Presence of other endocrine diseases

Differential Diagnosis

  • Sick euthyroid syndrome
  • Thyroiditis
  • Depression
  • Hypochondriasis
  • Nephrotic syndrome
  • Chronic nephritis
  • Addison’s disease
  • Hypopituitarism
  • Neurasthenia
  • Chronic fatigue syndrome
  • Fibromyalgia
  • Congestive heart failure (CHF)
  • Primary amyloidosis
  • Dementia from other causes
  • Infertility
  • Menopause
  • Ovarian insufficiency
  • Obesity
  • Sleep disorders

Investigation and Workup

History and Physical:

History and physical examination will provide definitive information in severe cases, but the disease can often be asymptomatic or have non-specific signs and symptoms. However; biochemical proof of thyroid hormone deficiency is necessary for diagnosis.


Laboratory studies:

  • Common tests of thyroid function include TSH, free T4, anti-thyroid peroxidase (anti-TPO) antibodies (see figure)
  • Serum thyrotropin hormone (TSH) measurement is the first-line diagnostic test
  • An elevated TSH level should be confirmed by a repeated measurement, along with measurement of serum free T4 estimates
  • Many patients with primary hypothyroidism have normal circulating levels of T3
  • Free T4 assays can be unreliable in the setting of severe illness

Common Tests of Thyroid Function-Investigations-Hypothyroidism

Interpretation of test results:

Although most laboratories report the upper range of normal for TSH is 4.5 mIU/L, evidence suggests that the true upper limit of normal may be as low as 2.5 mu/L.
Ref: Wartofsky, L. The evidence for a narrower thyrotropin reference range is compelling. The Journal of Clinical Endocrinology & Metabolism, 90:5483-5488, 2005.

Overt primary hypothyroidism:

  • TSH: Increased
  • Serum free thyroxine (T4): Decreased

Subclinical hypothyroidism:

  • TSH: Elevated (usually <10 mlU/L)
  • Serum free T4: Normal

Secondary or tertiary hypothyroidism:

  • TSH: Low or normal
  • Serum free T4: Decreased
  • Impaired TSH response to TRH

Antithyroid antibodies:

Anti-Thyroid peroxidase (TPO) antibodies

  • Useful to establish an autoimmune etiology of hypothyroidism in selected cases
  • Useful in predicting progression of subclinical to overt hypothyroidism

Imaging Studies

Ultrasound (thyroid):

  • Detect nodules and infiltrative disease
  • Useful in follow-up for the size of thyroid and nodules

MRI of the pituitary gland/hypothalamus:

  • When central hypothyroidism is suspected


a) Management of Hypothyroidism
     Goals: Restore and maintain euthyroid state as reflected by TSH levels.

Agent of choice:

  • Levothyroxine once daily, on an empty stomach
  • Recommend: High quality (same brand) of levothyroxine to be prescribed throughout the therapy, the reason being bioequivalence and brand interchangeability has not been proven among different brands

Treatment: Is individualized considering age, weight and cardiac status (see figure below)

Monitor treatment: Every 6 to 8 weeks until TSH is normalized, then at 6 months initially followed by annual assessments.

Drugs that interfere with thyroid hormone absorption:

  • Iron
  • Calcium carbonate
  • Cholestyramine
  • Lithium
  • Aluminum hydroxide gel
  • Sucralfate
  • Dietary soy

Medical conditions that may interfere with thyroid hormone absorption:

  • Gastrointestinal malabsorptive disorders
  • Previous small-bowel bypass surgery

Levo dosing-Treatment-Hypothyroidism

b) Management of subclinical hypothyroidism:

Individuals having a mild increase in TSH (usually <10 mUI/L), with normal free T4 and T3, and who may or may not be symptomatic; ~3-20% of these cases, may progress to (overt hypothyroidism)

Treatment is indicated in patients with:

– TSH >10 mIU/ml

– TSH above normal (4.5 to 10 mUl/L) with a goiter or anti-TPO antibodies, pregnancy, infertility, signs or symptoms or evidence of atherosclerotic cardiovascular disease, heart failure, or risk factors for these diseases


  • Starting dosage: 25-50 mcg/d (see figure)
  • Monitor TSH in 6-8 weeks and the dose should be adjusted accordingly
  • Target TSH value is between 0.3-3.0 mIU/ml
  • Once the disease is stabilized annually asses the patient

c) Management of Hypothyroidism during Pregnancy:

Hypothyroidism in pregnancy is associated with:

  • Preeclampsia
  • Anemia
  • Postpartum hemorrhage
  • Cardiac ventricular dysfunction
  • Spontaneous abortion
  • Low birth weight
  • Impaired cognitive development
  • Fetal mortality/ stillbirths

➣ Increased dosage requirements should be anticipated during pregnancy

  • Especially in the first and second trimesters

➣ Women with a history of treated hypothyroidism who are contemplating pregnancy should be rendered euthyroid with a goal TSH no higher than 2.5mUI/L before conception

➣ Patients with hypothyroidism should increase the levothyroxine dose by 30% to 50% by four to six weeks gestation

➣ For previously diagnosed women, serum TSH levels should be measured:

  • Every 4 weeks during the first half of pregnancy
  • At least once between 26 and 32 weeks gestation
  • At 6 weeks postpartum

➣ Levothyroxine dose should be adjusted:

  • To maintain a serum TSH less than 2.5 mIU/L, in the first trimester and <3.0 mUI/L in the second and third trimesters
  • The dose of levothyroxine may be returned to preconception levels immediately postpartum


  • DeGroot L, Abalovich M, Alexander E, et al. Management of thyroid dysfunction during pregnancy or postpartum: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism, 2012; 97:2543-2565
  • Romney JS. Treatment of subclinical hypothyroidism in pregnant women. CMAJ 2018,30;190:E545. doi: 10.1503/cmaj.733564
  • Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21:1-45

d) Hypothyroidism and concurrent diseases:

Diabetes mellitus:

  • Approximately 10% of type1 diabetes mellitus patients will develop chronic thyroiditis in their lifetime
  • Patients with diabetes should always be examined for goiter and regular TSH level monitoring should be done
  • Approximately 25% of women with type1 diabetes mellitus will develop postpartum thyroiditis


Typically patients seek medical attention for infertility or previous miscarriages, when investigated by a careful history, examination and labs will demonstrate clinical or subclinical hypothyroidism.

  • Patients with increased TSH levothyroxine replacement therapy will normalize the fertility issues


In patients with depression, clinical and subclinical hypothyroidism should always be considered.

  • Appropriate levothyroxine doses should be initiated in patients with elevated TSH levels

e) Management of myxedema coma: (Endocrine emergency)

  • Myxedema coma is an endocrine emergency and should be treated aggressively
  • Any precipitating factors should be treated
  • Administer mechanical ventilation if necessary
  • Parenteral hydrocortisone (50 mg every 6 hours)
    • Until coexisting adrenal insufficiency excluded
  • Intravenous Hypertonic saline and glucose
    • For severe Hyponatremia or hypoglycemia
  • Passive correction of hypothermia
    • Active correction can cause vasodilatation and hypotension

Preferred treatment:

  • Levothyroxine
    • 500 mcg IV, as a one-time loading dose
    • Subsequent daily dose: 50-100 mcg

Alternative treatment 1:

  • Tri-iodothyronine, T3
    • IV or via nasogastric tube, 10-25 mcg every 8-12 hours
    • Excess T3 may provoke arrhythmias

Alternative treatment 2:

  • Combined Levothyroxine (T4) and Tri-iodothyronine (T3)
    • Initial IV bolus levothyroxine (200 mcg) Tri-iodothyronine (25 mcg)
    • Subsequent daily doses of levothyroxine (50-100 mcg) and T3 (10 mcg every 8 h) until the patient responds
Thyroid agents
  • ➣ Levothyroxine


  • Exact mechanism of action is unknown
  • It is generally believed that they exert its many actions through control of DNA transcription and, ultimately, protein synthesis
  • Levothyroxine (T4) is a synthetic form of thyroxine, an endogenous hormone secreted by the thyroid gland. T4 is metabolically deiodinated to active metabolite, L-triiodothyronine (T3) in peripheral tissues



  • Usual initial dose ~1.7 mcg/kg/day PO once daily; usual doses are ≤200 mcg/day; may titrate dose by 12.5-25 mcg (every 6-8 weeks); Max. 300 mcg/day

Age >50 years or <50 years with the cardiac disease

  • Usual initial dose is 25-50 mcg/day; may titrate dose at 6-8 weeks intervals, as needed

Age >50 years with cardiac disease

  • Usual initial dose is 12.5-25 mcg/day; may titrate dose at 4-6 weeks interval, as needed

Subclinical hypothyroidism

  • Start with 25-50 mcg/day; may titrate dose at 6-8 week intervals as needed

Pipeline Agents

Pending new data.

Physician Resources

1. Tips for patient care

Risk factor management:

  • Advise patient to report signs of infection or potential heart problems (palpitations, dyspnea)
  • Hypothyroidism could increase the risk of infertility and miscarriage
  • If suspecting the presence of adrenal insufficiency, it should be confirmed or ruled out and should be treated prior to treatment of hypothyroidism
  • Generally, routine surgery in a hypothyroid patient should be deferred until euthyroidism is restored
  • Diabetic patients may need a readjustment of hypoglycemic agents with the institution of thyroxine
  • High-bulk diet may help avoid constipation
  • Educate patient about myxedema coma


  • Monitor TSH levels every 6 to 8 weeks until normalized, then at 6 months, followed by annual assessments
  • An elevated TSH level should be confirmed by a repeated measurement, along with measurement of serum free T4
  • If treatment in subclinical hypothyroidism is not initiated, then monitor with annual TSH and free T4 measurement
  • Follow cardiac status closely in elderly patients


  • Advise patient to establish the prescribed routine for pill-taking
  • Educate about the importance of drug therapy compliance
  • Appreciate lower starting doses of drugs in elderly and debilitated patients
  • Consider concurrent risk factors and disease states with the prescribed therapy
  • Levothyroxine is usually the first choice of treatment
  • Thyroid hormone has a narrow toxic-to-therapeutic ratio
    • Must be titrated on the basis of laboratory tests and clinical responses
  • Avoid over-replacement with thyroid hormone

Social and Stress factors:

  • Ensure patient and family are well informed about the disease and its treatment
  • Individuals with hypothyroid should be regularly screened for subclinical psychological distress and psychiatric disorders


  • Iron supplements frequently decrease levothyroxine absorption; caution required especially when iron supplements are prescribed due to increased demand for iron during pregnancy
  • Thyroid hormone replacement can precipitate adrenal crises in patients with untreated adrenal insufficiency
  • Relapses will occur if treatment is interrupted

Activities (physical, mental, others):

  • Stress on the importance of staying active and having a regular exercise routine
  • Advise patients to keep themselves mentally active

Myxedema coma:

  • Myxedema coma is a medical emergency
  • Untreated hypothyroidism may progress to myxedema coma
  • Identify and treat the precipitating factors of myxedema coma, such as hypoglycemia, infection, medications, cold exposure
  • A random cortisol level should be drawn prior to therapy
  • Administer hydrocortisone until coexisting adrenal insufficiency is ruled out
  • Deterioration of the patient’s mental status is one of the key manifestations of myxedema coma

Hypothyroidism and Pregnancy:

  • Hypothyroidism in pregnancy is safely and easily treated with synthetic thyroid hormone
  • Uncontrolled hypothyroidism during pregnancy can lead to, e.g.
    • Congestive heart failure, preeclampsia, miscarriage, low birth weight
    • Cognitive and developmental disabilities in the newborn
  • Levothyroxine requirements will likely increase during pregnancy. Monitor TSH level every 4-6 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation
  • Women with hypothyroidism should achieve good control prior to conception (TSH not more than 2.5mlU/L)
  • After delivery, most patients need to decrease the thyroxine dosage they received during pregnancy
  • There is an increased risk of developing permanent primary hypothyroidism in women with a history of postpartum thyroiditis

2. Scales and Table


Core Resources:

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Online Pharmacological Resources:

  • e-Therapeutics
  • Lexicomp
  • RxList
  • Epocrates

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