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Image : “Medical Needle shot” by Unknown. License: Public Domain

Definition of Hypothyroidism

Hypothyroidism refers to a group of clinical manifestations due to a decreased amount of circulating free T3 and T4 hormones. The condition is caused by a pathology involving the thyroid or hypothalamic-pituitary axis.

Subclinical hypothyroidism

Subclinical hypothyroidism is defined by elevated TSH level despite normal T3 and T4 levels.

Overt hypothyroidism

The presence of increased TSH with decreased free serum T3 and T4 values indicates overt hypothyroidism.

Thyroid System

Image: “Overview of the thyroid system” by Mikael Häggström. License: Public Domain

Epidemiology of Hypothyroidism

Hypothyroidism caused by iodine deficiency is more prevalent in less-developed countries. It usually affects females more than males and is common in elderly patients. Hypothyroidism is more common in Caucasians and Hispanics than in African Americans.

Etiology and Pathophysiology of Hypothyroidism

Hypothyroidism results from a deficiency in thyroid hormones. Any aberration in the hypothalamic-pituitary axis can decrease thyroid hormone production. Based on the deficiency site, it can be either primary or secondary hypothyroidism.

Primary hypothyroidism results when the primary pathology lies in the thyroid. Secondary hypothyroidism is caused by a pathology in the anterior pituitary. It may also be due to the deficiency of the thyrotropin-releasing hormone from the hypothalamus.

Causes of primary hypothyroidism

Iodine deficiency

Chronic autoimmune causes

  • Hashimoto’s disease


  • Thyroidectomy
  • Radioiodine therapy

Transient hypothyroidism

  • Painless thyroiditis
  • Postpartum thyroiditis
  • Subtotal thyroidectomy
  • Following radioiodine therapy in Graves’ disease


  • Thioamides
  • Amiodarone
  • Lithium


  • Thyroid agenesis
  • Thyroid dysgenesis

Causes of secondary hypothyroidism/central hypothyroidism


  • Tumors
  • Trauma

Clinical Presentation of Hypothyroidism

Clinical manifestations in hypothyroidism are primarily due to thyroxine deficiency. Symptoms usually are due to the decreased metabolic process and the accumulation of glycosaminoglycans.

Pathophysiologic mechanism(s) Symptoms Signs
Decreased metabolic rate
  • Fatigue
  • Cold intolerance
  • Exertional dyspnea
  • Weight gain
  • Growth failure
  • Constipation
  • Infantile mental retardation
  • Delayed relaxation of reflexes
  • Bradycardia
Accumulation of Glycosaminoglycans
  • Dry Skin
  • Hoarseness of voice
  • Edema
  • Periorbital edema
  • Macroglossia
  • Facial puffiness
Miscellaneous mechanisms
  • Menorrhagia
  • Delayed puberty
  • Myalgia
  • Depression
  • Pericardial effusion
  • Ascites
  • Galactorrhea
Symptoms and signs of hypothyroidism

Image: “Symptoms and signs of hypothyroidism,” by Mikael Häggström. License: CC0 1.0

Skin manifestations

  • Non-pitting edema
  • Alopecia
  • Dry skin
  • Cool extremities

Decreased peripheral circulation is the reason for cool extremities. The epidermis shows atrophy and hyperkeratosis, resulting in the characteristically dry skin.

Cardiovascular manifestations

Hypothyroidism results in decreased myocardial contractility and heart rate, which, in turn, leads to decreased cardiac output. The hypometabolic state in hypothyroidism is a consequence of reduced cardiac output.

Cardiovascular manifestations also include lower exercise tolerance and exertional dyspnea. Hypothyroidism in patients with existing heart disease leads to the worsening of angina and heart failure.

Other abnormalities contributing to cardiovascular diseases that may occur in hypothyroidism patients are:

Hematologic manifestations

Hypothyroidism results in hyperproliferative anemia, which is normocytic and normochromic.

Gastrointestinal manifestations

Constipation and decreased gastrointestinal motility are the most common symptoms of hypothyroidism.

Reproductive system manifestations

Women suffer from menorrhagia, which gradually progresses to oligomenorrhea and amenorrhea. Men face decreased libido, erectile dysfunction, and delayed ejaculation. There is a decrease in the concentration of sex hormone-binding globulin in hypothyroidism, which eventually leads to a lower total concentration of sex hormones; however, a normal concentration of free sex hormones is observed.

Musculoskeletal manifestations

Carpal tunnel syndrome (CTS)

The compression of the median nerve in the carpal tunnel is called carpal tunnel syndrome. There is a mucinous infiltration of the endoneurium and perineurium, along with mucopolysaccharides protein complex deposits on the tendons. This increases the intra-compartmental pressure, leading to carpal tunnel syndrome.

The presentation of CTS usually involves the presence of tingling and numbness, which increase gradually during the night. Weakness and thenar muscle atrophy also occur. The first three fingers and half of the fourth finger show a predominant sensory loss. It is a reversible feature in hypothyroidism, and symptoms improve upon resolution of hypothyroidism.

Other non-specific symptoms observed are joint aches and muscle stiffness.

Respiratory system manifestations

Sleep apnea is commonly seen in hypothyroidism, mostly because of macroglossia.

Metabolic abnormalities

  • Lipid profile: there are increased total and low-density lipoprotein levels due to decreased metabolism, resulting in decreased clearing of circulating lipids.
  • The level of homocysteine in the blood is increased in hypothyroidism.
  • Hyponatremia is usually observed in hypothyroidism because of decreased free water clearance. This needs to be ruled out while evaluating the syndrome of inappropriate antidiuretic hormone (SIADH).

Laboratory Evaluation and Diagnosis of Hypothyroidism

TSH measurement is the primary starting point of evaluating hypothyroidism. Increased TSH needs to be confirmed by estimating free T4.

Primary hypothyroidism is diagnosed by the presence of:

  • Increased TSH
  • Decreased T3
  • Decreased T4
  • Decreased rT3

If the TSH is decreased with a normal T3 and T4, it indicates subclinical hypothyroidism.

Testing for thyroid peroxidase antibodies is indicated in subclinical hypothyroidism to assess the need for pharmacotherapy. Thyroid peroxidase antibodies help diagnose autoimmune causes, especially Hashimoto’s disease.

Secondary hypothyroidism shows normal/low TSH levels with decreased free T4. Free T4 levels are significant in the diagnosis of secondary hypothyroidism.

Therapy and Treatment of Hypothyroidism

The aims of the pharmacotherapy are:

  • Symptomatic improvement
  • TSH normalization
  • Decreased goiter size (in autoimmune thyroiditis)

Synthetic T4 is the treatment of choice for hypothyroidism. It is continued for a person’s lifetime unless the etiology is due to transient hypothyroidism or drug-induced hypothyroidism (amiodarone & lithium administration). Withdrawal of the precipitating drug is recommended under these conditions.

T4 is a prohormone. It is converted to T3 after deiodination in the peripheral tissues based on the metabolic requirements of the patient.


1.6 mcg/kg body weight is the required dosage in young and healthy patients. The starting dose of 25 mcg is preferred in the elderly and should be titrated gradually based on the response.

Monitoring and dose adjustments

Symptomatic improvement usually occurs after two weeks, while TSH values take six weeks to establish a steady-state. Hence, TSH values should be measured after six weeks, and the dose should be adjusted.

Subclinical Hypothyroidism

It is characterized only by a biochemical alteration in the TSH value with no clinical symptoms. If the TSH value is less than 10 mIU/L, monitoring  TSH is advised every three months without treatment.

Treatment is required for the following presentations:

  • In pregnancy or planning for pregnancy
  • In patients with evidence of cardiac disease
  • In patients with TPO +ve antibodies

Subclinical hypothyroidism is treated by the administration of synthetic T4 (25 mcg).

Hashimoto’s Disease

It may present as goitrous and atrophic autoimmune thyroiditis. The pathogenesis involves high concentrations of antibodies to thyroid peroxidase and thyroglobulin. It usually has a higher prevalence in females.

The clinical course of Hashimoto’s disease involves a gradual loss of thyroid function. The initial presentation is subclinical hypothyroidism (TSH elevation with normal T4 and T3), which will eventually progress to overt hypothyroidism. Overt hypothyroidism usually persists throughout one’s lifetime, except in the case of children or pregnant women, who show only transient changes that will return to normal.


Inflammation in the earlier stages and follicular atrophy shows a gradual progression of follicular rupture. There is an increased release of the thyroid hormone into the circulation, leading to transient hyperthyroid symptoms.

Histopathology characteristically shows lymphocytic infiltration, lymphoid germinal centers, and epithelial hurthle cell changes. There is gradual follicular destruction as the disease progresses. Association with HLA-DR 5 is observed. Patients with Hashimoto’s thyroiditis have an increased risk of Non-Hodgkin’s lymphoma.

Antibodies against the following thyroid antigens are associated with Hashimoto’s disease:

  • Thyroglobulin (Tg)
  • Thyroid peroxidase (TPO)
  • Thyroid-stimulating hormone receptor

Histopathological Examination

It is significant in the diagnosis of Hashimoto’s thyroiditis (chronic autoimmune thyroiditis). It is characterized by lymphocytes infiltrating the thyroid follicles, which gradually leads to thyroid failure and goiter formation.

Hashimoto's thyroiditis with lymphoid infiltration

Image: “Hashimoto’s thyroiditis with lymphoid infiltration. Autoantibodies against thyroid peroxidase and thyroglobulin were elevated,” by Patho. License: CC BY-SA 3.0

Drug-Induced Hypothyroidism


Amiodarone, a class III antiarrhythmic drug with two iodine atoms in its structure, can be administered to treat both hypothyroidism and hyperthyroidism. Amiodarone inhibits the entry and peripheral conversion of T4 to T3.

Effects of amiodarone on the thyroid gland include:

  1. Hypothyroidism: The mechanism involves decreasing the peripheral conversion of T4 to T3 (inhibits 1 5′-deiodinase enzyme activity) and inhibits T4 and T3 entering into the peripheral tissue.
  2. There are two types of effects:
    • Type 1: there is an increased synthesis of thyroid hormone as amiodarone acts as a substrate.
    • Type 2: there is autoimmune destructive thyroiditis due to the direct toxic effect of amiodarone on the follicular epithelial cells.
Thyroide gland

Image: “Scheme of the thyroid gland,” by Arnavaz. License: Public Domain


Lithium is the treatment of choice for bipolar disorder. Hypothyroidism usually develops within two years of treatment with lithium. Screening for hypothyroidism should be performed while initiating the lithium treatment. The hypothyroidism is usually sub-clinical and gradually progresses to overt hypothyroidism. Treatment with lithium also causes goiter.

Mechanism: there is increased intrathyroidal content due to treatment with lithium. Increased iodine decreases the coupling of iodine in the formation of T4 and T3. There is no indication to discontinue lithium treatment due to hypothyroidism. Instead, hypothyroidism needs to be treated.

Congenital hypothyroidism

3 month old infant with untreated CH

Image: “3-month-old infant with untreated CH. The picture demonstrates hypotonic posture, myxedematous facies, macroglossia and umbilical hernia,” by Rastogi and LaFranchi; licensee BioMed Central Ltd. License: CC BY 2.5

The most common cause of congenital hypothyroidism is thyroid dysgenesis. There are minimal clinical manifestations at birth due to the presence of maternal T4 which crossed the placenta.

Signs and symptoms include:

  • Macroglossia
  • Umbilical hernia
  • Hoarse cry
  • Lethargy
  • Increased size of the fontanels
  • Prolonged jaundice
  • Hypotonia


Screening is performed by collecting a heel prick blood sample, typically two to five days after delivery. The sample is assayed for initial T4 levels, followed by a TSH assay if T4 values are below the 10th percentile. If the screening test is positive, retesting of serum TSH and T4 is conducted by collecting a blood sample by venipuncture.


Administer synthetic T4 with a dosage of 10—15 µg/kg per day.

Central Hypothyroidism/Secondary Hypothyroidism

Hypothyroidism due to central causes occurs when there is a primary pathology in the pituitary, hypothalamus, or hypothalamic-pituitary axis.


  • Tumors
  • Pituitary adenoma
  • Pituitary adenocarcinoma
  • Craniopharyngioma
  • Meningioma
  • Metastatic secondaries
  • Infiltrative disorders
  • Hemochromatosis
  • Tuberculosis
  • Syphilis
  • Iatrogenic
  • Radiotherapy
  • Surgery

Pituitary adenomas are the most common cause of central hypothyroidism.

Clinical features are similar to primary hypothyroidism with coexisting excesses or deficiencies of other pituitary hormones.

Thyroid function tests show:

  • Free T4: Low or Normal
  • Free T3: Low
  • TSH: Low or Normal

Serum TSH may be low, normal, or even slightly elevated (up to about 10 mIU/L) in some patients because of reduced biological activity with normal immunoactivity (due to abnormal glycosylation of TSH subunits).


Administration of synthetic T4 (dose of 1.6µg/kg). Dose titration is based on monitoring serum-free T4 values and the patient’s symptoms.

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10 thoughts on “Hypothyroidism (Underactive Thyroid) — Medication and TSH Levels

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