Table of Contents
- Definition of Hypothyroidism
- Epidemiology of Hypothyroidism
- Etiology and Pathophysiology of Hypothyroidism
- Clinical Presentation of Hypothyroidism
- Laboratory Evaluation and Diagnosis of Hypothyroidism
- Therapy and Treatment of Hypothyroidism
- Subclinical Hypothyroidism
- Hashimoto’s Disease
- Drug-Induced Hypothyroidism
- Central Hypothyroidism/Secondary Hypothyroidism
- Review Questions
Definition of Hypothyroidism
Hypothyroidism is a group of clinical manifestations due to a decreased amount of circulating free T3 and T4 hormones, caused by a pathology involving the thyroid or hypothalamic-pituitary axis.
Presence of increased TSH with normal serum T3 and T4 is called subclinical hypothyroidism.
Presence of increased TSH with decreased free serum T3 and T4 values indicates overt hypothyroidism.
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 caused by a pathology in the anterior pituitary or is due to the deficiency of the thyrotropin-releasing hormone from the hypothalamus.
Causes of primary hypothyroidism
Chronic autoimmune causes
- Hashimoto’s disease
- Radioiodine therapy
- Painless thyroiditis
- Postpartum thyroiditis
- Subtotal thyroidectomy
- Following radioiodine therapy in Graves’ disease
- Thyroid agenesis
- Thyroid dysgenesis
Causes of secondary hypothyroidism/central hypothyroidism
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.
|Decreased metabolic rate||
|Accumulation of Glycosaminoglycans||
- Nonpitting edema
- 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.
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:
Hypothyroidism results in hyperproliferative anemia, which is normocytic and normochromic.
Constipation and decreased gastrointestinal motility are the 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.
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 increase 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.
- Lipid profile: There are an increased total and low-density lipoprotein levels. It is 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 for the 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. 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 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.
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.
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 patients with evidence of cardiac disease
- In patients with TPO +ve antibodies
Subclinical hypothyroidism is treated by administration of synthetic T4 (25 mcg).
It may 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 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 one’s lifetime, except in the case of children or pregnant women who show only transient changes which 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 hurtle cell changes. There is gradual follicular destruction as the disease progresses. Association with HLA-DR 5 is observed. There is an increased risk of Non-Hodgkin’s lymphoma in Hashimoto’s thyroiditis.
Antibodies against the following thyroid antigens are associated with Hashimoto’s disease:
- Thyroglobulin (Tg)
- Thyroid peroxidase (TPO)
- Thyroid stimulating hormone receptor
It is significant in the diagnosis of Hashimoto’s thyroiditis (chronic autoimmune thyroiditis). It is characterized by infiltration of the thyroid follicles with lymphocytes, which gradually leads to thyroid failure and goiter formation.
Amiodarone is a Class III antiarrhythmic drug with 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 the thyroid gland include:
- 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.
- It is of two types:
- 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.
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 subclinical and 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 T3.
There is no indication of discontinuation of lithium treatment due to hypothyroidism. Instead, hypothyroidism needs to be treated.
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:
- Umbilical hernia
- Hoarse cry
- Increased size of the fontanels
- Prolonged jaundice
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.
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 the pituitary, hypothalamus or hypothalamic-pituitary axis.
- Pituitary adenoma
- Pituitary adenocarcinoma
- Metastatic secondaries
- Infiltrative disorders
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 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).
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.
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?
- Administration of synthetic T4.
- Administration of synthetic oxytocin.
- Administration of synthetic melatonin.
- Administration of synthetic throtropin-releasing hormone.
- Administration of synthetic gonadotropin-releasing hormone.
2. Which of the following statements about hypothyroidism is NOT correct?
- It most commonly affects white people and Mexican Americans.
- Hypothyroidism is caused by the deficiency of T3 and T4.
- Pituitary adenomas are the most common cause of central hypothyroidism.
- Administration of synthetic T4 is the treatment of choice for hypothyroidism.
- Telmisartan can cause drug-induced hypothyroidism.
3. Which of the following symptoms is not associated with cardiovascular manifestations observed in hypothyroidism?
- Decreased exercise tolerance
- Decreased exertional dyspnea
- Decreased myocardial contractility
- Decreased heart rate
- Nonpitting edema