Hypothyroidism is caused by the deficiency of T3 and T4. Hashimoto disease (autoimmune thyroiditis) is the leading cause of hypothyroidism in non-iodine deficient regions. Clinical features of hypothyroidism are primarily due to the accumulation of matrix substances and a decreased metabolic rate. Hypothyroidism is diagnosed by estimation of TSH and free T4. It is treated by administration of synthetic T4.

Are you more of a visual learner? Check out our online video lectures and start your pathology course now for free!

Posterior thyroid

Image: “The human thyroid as viewed from the front, with arteries visible.
Note the superior thyroid artery, which supplies the thyroid with much of its blood.” by CFCF. License: CC BY-SA 3.0


Definition of Hypothyroidism

Clinical manifestations due to a decreased amount of circulating free T3 and T4 hormones usually due to a pathology involving the thyroid or hypothalamic pituitary axis are called hypothyroidism.

Subclinical hypothyroidism

Presence of increased TSH with normal serum T3 and T4 is called subclinical hypothyroidism.

Overt hypothyroidism

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 white people 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 result in decreased thyroid hormone production. Based on the site of the deficiency, it can be either primary or secondary hypothyroidism.

Primary hypothyroidism results when the primary pathology lies in the thyroid.

Secondary hypothyroidism is due to pathology in the anterior pituitary or due to the deficiency of the thyrotropin-releasing hormone from the hypothalamus.

Causes of primary hypothyroidism

Iodine deficiency

Chronic autoimmune causes

  • Hashimoto’s disease

Iatrogenic

  • Thyroidectomy
  • Radioiodine therapy

Transient hypothyroidism

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

Drug induced

  • Thioamides
  • Amiodarone
  • Lithium

Congenital

  • Thyroid agenesis
  • Thyroid dysgenesis

Causes of secondary hypothyroidism/central hypothyroidism

Hypopituitarism

  • Tumors
  • Trauma

Clinical Presentation of Hypothyroidism

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

  • Nonpitting edema
  • Alopecia
  • Dry skin
  • Cool extremities

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

Cardiovascular manifestations

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

Cardiovascular manifestations also include decreased exercise tolerance and exertional dyspnea. Hypothyroidism in patients with existing heart disease leads to 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 most common symptoms observed in hypothyroidism.

Reproductive system manifestations

Women suffer from menorrhagia, which is gradually progressing 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 the decreased total concentration of sex hormones; however, a normal concentration of free sex hormones is observed.

Musculoskeletal manifestations

Carpal tunnel syndrome (CTS)

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 deposition on the tendons. This increases the intra-compartmental pressure, leading to the carpal tunnel syndrome.

Presentation of CTS usually involves the presence of tingling and numbness which increases gradually during the night. Weakness and thenar muscle atrophy are also observed.  First three fingers and half of the fourth finger show a predominant sensory loss. It is a reversible feature in hypothyroidism and symptoms improve on the resolution of hypothyroidism.

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

Respiratory system manifestations

Sleep apnea is commonly seen in hypothyroidism. This is predominantly due to macroglossia.

Metabolic abnormalities

  • Lipid profile: There is an increased total and low density lipoprotein levels. It is due to decreased metabolism resulting in decreased clearing of circulating lipids.
  • Level of homocysteine in the blood is increased in the hypothyroidism.
  • Hyponatremia is usually seen in hypothyroidism due to decreased free water clearance. This needs to be ruled out while evaluating syndrome of inappropriate antidiuretic hormone (SIADH).

Laboratory Evaluation and Diagnosis of Hypothyroidism

Measurement of TSH is the primary investigation in the evaluation of hypothyroidism. Decreased TSH needs to be confirmed by the estimation of 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 in the diagnosis of 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
  • Normalization of TSH
  • Decrease in the size of the goiter (in autoimmune thyroiditis)

Administration of synthetic T4 is the treatment of choice for hypothyroidism. Treatment of hypothyroidism is continued till lifetime unless the etiology is due to transient hypothyroidism or drug induced hypothyroidism (amiodarone & lithium administration). Withdrawal of the precipitating drug is recommended in 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.

Dosage

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

Monitoring and dose adjustments

Symptomatic improvement usually occurs after 2 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 the TSH is advised every 3 months without treatment.

Treatment is required for the following presentations:

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

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

Hashimoto’s Disease

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

The clinical course of the Hashimoto’s disease involves gradual loss of thyroid function. Initial presentation involves the presence of subclinical hypothyroidism (TSH elevation with normal T4 and T3) which will show an eventual progression to overt hypothyroidism. The overt hypothyroidism usually persists throughout the lifetime, except in the case of children or pregnant women. They show only transient changes which will return to normal.

Hashitoxicosis

Inflammation in the earlier stages and follicular atrophy shows a gradual progression to 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 centres and epithelial hurthle cell changes. There is gradual follicular destruction as the disease progresses. Association with HLA-DR 5 is seen. There is an increased risk of Non-Hodgkin’s lymphoma in hashimotos thyroiditis.

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 hashimotos thyroiditis (chronic autoimmune thyroiditis). It is characterized by infiltration of the thyroid follicles with lymphocytes, 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

Amiodarone is a Class III antiarrythmic drug which has two iodine atoms in its structure. Administration of amiodarone can be presented as both hypothyroidism and hyperthyroidism. Amiodarone inhibits the entry and peripheral conversion of T4 to T3.

Effects of amiodarone on thyroid gland:

  1. Hypothyroidism: Mechanism involves…
    • …decreasing peripheral conversion of T4 to T3 (inhibits 1 5′-deiodinase enzyme activity).
    • …inhibiting entry of T4 and T3 into the peripheral tissue.
  2. It is of two types:
    • Type 1: There is an increased synthesis of thyroid hormone, as amiodarone act as a substrate.
    • Type 2: There is autoimmune destructive thyroiditis due to direct toxic effect of amiodarone on follicular epithelial cells.
Thyroide gland

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

Lithium

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 treatment of lithium. The hypothyroidism is usually subclinical which gradually progresses to overt hypothyroidism. Treatment with lithium also causes goiter.

Mechanism: There is an increased intrathyroidal content due to treatment with lithium. Increased iodine decreases the coupling of iodine in the formation of T4 and T4.
There is no indication of discontinuation of 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; 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

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

Treatment

It involves administration of 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 pituitary, hypothalamus or hypothalamic pituitary axis.

Etiology

  • 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 the primary hypothyroidism with coexisting excess or deficiencies of other pituitary hormones.

Thyroid function tests shows:

  • 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).

Treatment

By administration of synthetic T4 (dose of 1.6µg/kg). Dose titration is based on the monitoring of free T4 values. The dose is to be increased based on the patient’s symptoms and on the serum-free T4 values.

Review Questions

The correct answers are below the references.

1. A 65-year-old male patient of Mexican-American descent presents to the clinic. The noted symptoms are fatigue, cold intolerance, weight gain, edema and hoarseness of voice. Cardiovascular manifestations such as decreased cardiac output and heart rate are also observed. After analyzing lab reports, hypothyroidism is diagnosed. What is the most suitable therapy for the patient?

  1. Administration of synthetic T4.
  2. Administration of synthetic oxytocin.
  3. Administration of synthetic melatonin.
  4. Administration of synthetic throtropin-releasing hormone.
  5. Administration of synthetic  gonadotropin-releasing hormone.

2. Which of the following statements about hypothyroidism is NOT correct?

  1. It most commonly affects white people and Mexican-Americans
  2. Hypothyroidism is caused by the deficiency of T3 and T4
  3. Pituitary adenomas are the most common cause of central hypothyroidism
  4. Administration of synthetic T4 is the treatment of choice for hypothyroidism
  5. Telmisartan can cause drug-induced hypothyroidism

3. Which of the following symptoms are not associated with cardiovascular manifestations observed in hypothyroidism?

  1. Decreased exercise tolerance
  2. Decreased exertional dyspnea
  3. Decreased myocardial contractility
  4. Decreased heart rate
  5. Nonpitting edema
Lecturio Medical Courses

Leave a Reply

Your email address will not be published. Required fields are marked *