Hypothyroidism: Pathophysiology and Management

Abstract

The thyroid plays an essential role in the homeostasis of the human body. Its hormones, thyroxine (T4) and triiodothyronine (T3), affect nearly every cell by regulating basal metabolism, protein synthesis, and growth and development. Hypothyroidism is a result of thyroid hypofunction. It can be described as a primary or central disorder. Primary disorders are dysfunctions of the thyroid gland itself, whereas central disorders occur due to disruptions in the HPT axis. Primary hypothyroidism has a higher incidence compared to central. It is predicted that 4.6% of Americans have hypothyroidism without knowing. Therefore, it is integral for healthcare providers to recognize and treat hypothyroidism to prevent morbidity. Clinical manifestations are nonspecific but play a role in determining the diagnosis, severity, and treatment strategies. Diagnosis is made with TSH and serum free T4 levels. Through adequate treatment, patients can achieve symptom resolution and euthyroidism. This chapter describes the epidemiology, etiology, pathophysiology, clinical manifestations, and treatments of hypothyroidism.

1. Introduction

The thyroid plays an essential role in maintaining homeostasis of the body. Its function is regulated by the hypothalamic-pituitary-thyroid (HPT) axis and the associated feedback loops. The hypothalamus synthesizes and secretes thyrotropin-releasing hormone (TRH) which activates the release of thyroid-stimulating hormone (TSH) by pituitary thyrotrophs. TSH binds to the receptor on the thyroid gland and stimulates the synthesis and secretion of thyroid hormones (TH). The thyroid is composed of two main endocrine cell types, follicular cells and parafollicular C-cells. C-cells produce calcitonin which couples with parathyroid hormone to maintain serum calcium. However, this will not be discussed further as it is beyond the scope of this review of hypothyroidism [1]. The follicular cells are responsible for producing both inactive thyroxine (T4) and active triiodothyronine (T3) with a circulating T4:T3 ratio of 13:1–16:1 [2]. Serum TSH levels are determined by TRH stimulation, negative feedback with T3, temperature, and diurnal pulse secretion. About 80% of T3 is generated in peripheral tissues via conversion of T4 by deiodinase enzymes, and it is considered the active hormone due to its ten-fold greater affinity for thyroid hormone receptors compared to T4 [3]. TH influences almost every cell in the body to regulate basal metabolism, protein synthesis, as well as growth and development [4].

Thyroid dysfunction is categorized as primary or central. Primary disorders result from dysfunction of the thyroid gland itself, whereas central disease states occur due to disruption of the hypothalamic-pituitary-thyroid axis [3]. Alternatively, thyroid disorders may be classified as physiologic, anatomical, and mixed.

According to the American Thyroid Association (ATA), it is estimated that 20 million Americans have a thyroid disorder with almost 60% being unaware of the presence. The ATA estimates that 1 in 8 women are likely to manifest a thyroid disease during their lifetime. Epidemiology estimates predict women are 5–8 times more prone than men to present with a thyroid disorder. Therefore, it is important for primary healthcare providers to be familiar with common thyroid disorders for early recognition and treatment options to prevent further morbidity associated with thyroid dysfunction.

Screening recommendations for thyroid dysfunction in asymptomatic adults vary wildly [5]. The American Academy of Family Physicians (AAFP) recommends screening subjects ≥60 years of age. Alternatively, the ATA recommends screening both women and men >35 years of age every 5 years. The American Association of Clinical Endocrinologists (AACE) recommends screening older patients without a specific age guideline, especially women. Lastly, the American College of Physicians (ACP) recommends screening in women ≥50 years of age with symptoms suggestive of thyroid disease [6]. Additionally, several organizations suggest assessment of thyroid function in pregnant women [7]. Utilizing any of the screening guidelines may be appropriate with good clinical judgment based on history, especially the presence of thyroid disorder in a family member, and a physical examination. Screening should be initiated in the presence of other manifestations including dyslipidemia, dementia, mental status changes, menstrual irregularities, atrial fibrillation, etc.

This review describes the epidemiology, etiology, pathophysiology, and clinical manifestations of hypothyroidism.

2. Epidemiology/etiology

Hypothyroidism is defined as high serum TSH in the presence of low serum-free T4. Hypothyroidism’s prevalence varies between 0.1% and 2.0%. However, it’s predicted around 4.6% of people in the United States have hypothyroidism without them knowing [8]. Women are up to 8-times more likely to have hypothyroidism compared to men. Other risk factors include personal or family history of autoimmune diseases, increased age, anti-thyroid peroxidase antibodies (TPOAb), genetic diseases like Down Syndrome or Turner Syndrome, and Caucasian and Asian ethnicities [8, 9, 10, 11, 12, 13]. The main cause of hypothyroidism in iodine-sufficient areas is Hashimoto’s thyroiditis, a chronic autoimmune disorder characterized by the formation of autoantibodies against the thyroid, leading to its destruction [14]. Other causes include excessive treatment of hyperthyroidism, the presence of a goiter, iodine deficiency or excess, and certain medications [15].

3. Clinical manifestations

Symptoms of hypothyroidism are nonspecific but can play a role in determining the diagnosis, severity, and treatment strategies of hypothyroidism [15]. See Table 1 for clinical signs and symptoms.

Organ system	Hypothyroidism	Hyperthyroidism
Constitutional	Fatigue, weight gain, cold intolerance	Heat intolerance, weight loss, goiter, fatigue
Skin	Dry or coarse skin, hair loss	Sweating, warm skin, onycholysis, softening of nails, hyperpigmentation, pruritis, thinning of hair
Neuromuscular	Muscle weakness, cramps, arthralgia, increased creatine kinase	Tremor, weakness
Cardiovascular	Decreased cardiac output, bradycardia, decreased contractility, decreased exercise capacity	Palpitations, tachycardia, systolic hypertension, cardiomyopathy, atrial fibrillation, mitral valve prolapse
Gastrointestinal	Decreased gut motility, constipation, decreased taste sensation, gastric atrophy, nonalcoholic fatty liver disease, ascites (rare)	Anorexia, vomiting, hyperdefecation, dysphagia due to goiter, increased liver function tests, abdominal tenderness
Metabolic	Hyponatremia, reversible serum creatin increases, hyperlipidemia	Osteoporosis, hyperglycemia, reduced HDL, gynecomastia in men
Hematologic	Pernicious anemia	Normochromic, normocytic anemia, increased clotting factors
Genitourinary	Menstrual irregularities, oligomenorrhea, amenorrhea, hypermenorrhea-menorrhagia, sexual dysfunction, decreased fertility	Urinary frequency, amenorrhea, reduced libido, decreased fertility
Neuropsychiatric	Slowed mentation, poor concentration, mood impairment	Agitation, depression, anxiety, confusion, poor concentration, nervousness, disturbed sleep

Table 1.

Signs and symptoms of hypo- and hyperthyroidism [16, 17, 18, 19].

4. Diagnosis

TSH levels must be drawn to make the clinical diagnosis since symptoms are nonspecific. High serum TSH above the upper limit of normal (ULN) with low serum T4 levels are seen in patients with hypothyroidism. The ULN depends on the laboratory but is commonly referenced as 4–5 miU/L. If a patient has hypothyroid symptoms, but normal TSH levels and low serum free T4 levels even after repeat, it may be due to central hypothyroidism [6]. TPOAb and thyroglobulin antibodies (TgAb) are positive in most patients with hypothyroidism due to Hashimoto’s thyroiditis [6]. TPOAb is not routinely measured to determine the diagnosis, however, situations that may be helpful to measure TPOAb include patients with a goiter in the absence of hypothyroidism, subclinical hypothyroidism, painless thyroiditis, or postpartum thyroiditis, as is discussed below. This can help predict the chance of progressing to overt hypothyroidism [6].

5. Management

The goals of treatment are symptoms resolution and to achieve euthyroidism. First line treatment for hypothyroidism is synthetic T4, levothyroxine. Most patients can meet their goals with T4 monotherapy. This results in fewer cardiovascular side effects compared to T3 and T4 therapy combined. Levothyroxine’s normal starting dose is 1.6 mcg/kg per day for adults. However, patients >60 years old or patients with coronary artery disease should be initiated at a lower dose of 12.5–25 mcg/day [20]. Additional situations that would call for lower doses are weight loss >10% of body weight and initiation of androgen therapy [20]. Alternatively, patients being treated with estrogen therapy or who are pregnant will require higher doses than usual patients. Patients with celiac or Crohn’s disease or a history of bariatric surgery may require higher doses as well due to decreased absorption [9].

Appropriate administration of thyroid hormone is important in achieving appropriate therapeutic levels. Levothyroxine should be taken on an empty stomach 30–60 minutes before breakfast around the same time each day. It is recommended to avoid changing between generic or brand name equivalents for levothyroxine due to variations in formulations in terms of potency and bioavailability.

Medications that can decrease levothyroxine absorption should be separated by 4 hours before or after administration [21]. Table 2 lists common medications that can impact levothyroxine levels [21, 22]. If administration habits are changed or a medication is added or discontinued, evaluating TSH levels and adjusting doses is necessary. Encouraging patients to let their providers know if medications have been added, stopped, or doses adjusted will also allow for better disease state management.

Decreases absorption	Bile acid sequestrants (cholestyramine, colestipol, colesevelam) Sucralfate Cation exchange resins (Kayexelate) Oral bisphosphonates Proton pump inhibitors Multivitamins (containing ferrous sulfate or calcium carbonate) Ferrous sulfate Phosphonate binders (sevelamer, aluminum, hydroxide) Calcium salts (carbonate, citrate, acetate) Chromium picolinate Charcoal Orlistat Ciprofloxacin
Increases clearance	Phenobarbital Primidone Phenytoin Carbamazepine Oxcarbazepine Rifampin Growth hormone Sertraline Tyrosine kinase inhibitors Quetiapine Stavudine
Peripheral metabolism	Amiodarone: impair conversion of T4 to T3 Glucocorticoids and some beta-blockers at high doses: impair conversion of T4 to T3 (may not be clinically relevant)

Table 2.

Medications that Impact Levothyroxine [6, 21] (derived from ATA/AACE Guidelines for Hypothyroidism).

Most patients taking levothyroxine tolerate it without adverse effects [20]. Headache, palpitations, and anxiety are common side effects, but they may be mitigated by starting at a lower dose and titrating slowly. Some major adverse effects that can occur with overcorrecting thyroid levels include atrial fibrillation and osteoporosis. In patients with dye hypersensitivity, the 50 mcg tablets can be used to avoid allergic reactions [20].

The idea of using combination therapy with both T4 and T3 is to mimic the normal 13:1–16:1 ratio in physiologic circulation [20]. The combination may be beneficial in patients in whom conversion of T4 to T3 in peripheral tissues is inhibited secondary to chronic illness, diets, or drugs. However, combination therapy is not currently recommended by either the ATA or AACE guidelines for most patients. There is a lack of evidence supporting the superiority of combination therapy compared to T4 monotherapy, even in patients who are still symptomatic on levothyroxine therapy [16, 20]. Certain situations may be appropriate to trial combination therapy, but patients should be closely monitored to avoid inducing hyperthyroidism. This includes patients on T4 monotherapy who are still symptomatic after a thyroidectomy or ablative therapy with radioiodine or have a serum T3 level that is subnormal. Combination therapy is better avoided in the elderly, pregnant patients, and anyone with the presence of cardiovascular disease [20].

Desiccated thyroid, also known as thyroid extract, is not a preferred treatment for hypothyroidism. It has not been shown to be superior to levothyroxine and there are clinical concerns with thyroid extracts. The ratio of T4 to T3 in desiccated thyroid is 4.2:1 compared to the ~14:1 secreted by the normal thyroid gland. The ratio poses the risk of supraphysiologic levels, and the shorter half-life causes greater fluctuations of T3 throughout the day. This can increase the risk of thyrotoxicosis if not carefully monitored [20].

Steady-state concentrations may not be achieved until 6 weeks of levothyroxine use; however, symptoms should improve within 2 weeks of therapy. It is recommended to measure serum TSH 6–8 weeks after initiating treatment and levothyroxine be titrated by 12.5–25 mcg depending on the TSH levels and subsequently rechecked after an additional 4–6 weeks [20]. Thereafter, follow-up visits at 6–12 month intervals suffice for monitoring. Assessing TSH sooner may be necessary with changes in the patient’s overall health status or if interacting medications are initiated or discontinued [20]. However, determining TSH alone may be counterproductive in patients with unreliable compliance. Determination of free T4 is helpful in assessing compliance, appropriate administration, as well as gastrointestinal absorption. It is important to note that after starting treatment for hypothyroidism, the metabolism of other medications may be increased and should be monitored closely as well, especially high-risk medications.

6. Pregnancy

Pregnancy increases the demands of thyroid hormone for proper development of the fetus. Overt hypothyroidism in pregnancy is defined as an elevated TSH and a decreased T4 outside of the trimester-specific normal ranges. Normal ranges as defined by the institutional laboratory should be adhered to for diagnosis of thyroid dysfunction. Serum TPOAb should be determined as its presence has been documented to increase the risk of pregnancy-related adverse outcomes [7].

Hypothyroidism in pregnancy increases the risk of several adverse outcomes including premature birth, low birth weight, decreased fetal neurocognitive development, and pregnancy loss. Therefore, prompt treatment of hypothyroidism is recommended. Evidence of treatment for subclinical hypothyroidism is not well defined. However, subjects with subclinical hypothyroidism and positive TPOAb are prone to increased risk of complications, and levothyroxine supplementation has been documented to improve outcomes [7].

Levothyroxine is the thyroid hormone of choice for hypothyroid treatment in pregnancy as well. T3 or desiccated thyroid must not be used due to an increased risk of attaining supraphysiologic levels of T3 and the inability of T3 to cross the fetal central nervous system. In patients already on levothyroxine, increases in doses may be required within 4–6 weeks of pregnancy. Levothyroxine requirements increase through 16–20 weeks due to a rise in thyroid hormone binding globulin caused by increasing circulating estrogen levels as well as enhanced renal clearance. According to the American Thyroid Association, a dose increase of 20–30% should be prescribed preemptively once pregnancy is confirmed prior to further testing. Monitoring TSH every 4 weeks until midgestation and at least once around 30 weeks is recommended [7]. The daily dose frequently declines over 3–4 weeks postpartum.

7. Subclinical hypothyroidism

Subclinical hypothyroidism is defined as elevated TSH with T4 levels in the normal range. Prevalence of this is greater than overt hypothyroidism with a rate of 4.3% in the National Health and Nutrition Examination Survey (NHANES III) and 8.5% in the Colorado Thyroid Prevalence Study [6]. Prevalence is higher in adults aged 65 years or older at a rate of 8–18% and it is more commonly seen in women compared to men [23]. Common causes include medications, thyroiditis, thyroid infiltration, and TSH gene mutation.

Treatment is controversial if TSH levels are 4.5–10 miU/L, but is usually recommended if >10 miU/L. The rationale for treatment includes prevention of progression to overt hypothyroidism and development of cardiovascular events, whereas consensus against treatment is based on the absence of data showing long-term progression in many patients, risk of overtreatment including hyperthyroid manifestations and complications such as arrhythmia and osteoporosis especially in the elderly, as well as the cost and commitment of lifelong therapy [24]. Levothyroxine is the preferred agent for subclinical hypothyroidism with similar monitoring as overt hypothyroidism but with a lower initiating dose. Depending on the TSH elevation, a daily dose of 25–75 mcg may be appropriate [6]. A randomized, double-blinded control trial looked for potential benefits of treating older adults with subclinical hypothyroidism. They found no difference in thyroid symptoms or a tiredness score between patients receiving treatment versus placebo at 6–8 weeks of treatment. Cardiovascular events were not measured since it was underpowered to determine this outcome [23]. However, several recent studies recommend attaining a serum TSH level between 5 and 10 miU/L in elderly patients as survival is longer with this TSH level in comparison to subjects achieving normal TSH concentrations [24, 25, 26, 27, 28, 29].

The presence of TPOAb can help decide whether to treat or not. It was found that patients with subclinical hypothyroidism and positive TPOAb levels have a 4.6% rate per year of progression to overt hypothyroidism compared to those with negative levels at 2.6% per year [6]. Overall, deciding to treat a patient or not should be based on the risks, benefits, patient preference, and clinical decision-making.

8. Hashimoto’s thyroiditis

Hashimoto’s thyroiditis is a chronic autoimmune disease that causes the destruction of the thyroid gland. It is the most common cause of hypothyroidism in iodine-sufficient areas [14, 30]. The clinical manifestations are similar to classic hypothyroidism symptoms. It is rare to have pain associated with Hashimoto’s thyroiditis [30].

Autoantibodies attack the thyroid gland causing it to lose function over time, leading to hypothyroidism. However, it is important to note that these autoantibodies may not be present in all cases. Checking TSH, TPOAb, and TgAb along with analyzing a thyroid ultrasound will help determine a Hashimoto’s thyroiditis diagnosis [30].

There is not one specific cause of Hashimoto’s thyroiditis, but it is more so thought to be due to both genetic and environmental factors. Specific genes that play a role in T cell function, thyroid development, and thyroid hormone enzymes have been identified among patients with Hashimoto’s. Other precipitating factors include high iodine intake, stress, radiation exposure, sex steroids, and infection [30].

The primary treatment of Hashimoto’s thyroiditis is targeted towards replenishing thyroid hormone since it causes destruction of the thyroid [30].

9. Conclusions

The thyroid is integral to the body’s ability to maintain homeostasis. Through the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) by the pituitary gland, thyroid hormones regulate basal metabolism, protein synthesis, and growth and development. Hypothyroidism is a thyroid gland disorder that can occur at the level of the thyroid or within the hypothalamic-pituitary-thyroid axis. Clinical manifestations of hypothyroidism include fatigue, weight gain, cold intolerance, hair loss, muscle cramps, constipation, menstrual irregularities, and slowed mentation.

Diagnosis cannot be made with symptoms only as they are nonspecific. With primary hypothyroidism, patients typically have high serum TSH and low serum T4 laboratory values. If a patient has hypothyroid symptoms, normal TSH, and low serum T4, it may be due to central hypothyroidism. Antibodies to thyroid peroxidase (TPOAb) or thyroglobulin (TgAb) indicate Hashimoto’s Thyroiditis, which is hypothyroidism due to the autoimmune destruction of the thyroid gland.

Treatment of hypothyroidism is focused on achieving euthyroidism. The first-line treatment for hypothyroidism is levothyroxine, which is a synthetic T4. T4 monotherapy is favored over T3 and T4 combination due to fewer cardiovascular side effects. Many medications affect the absorption, clearance, or metabolism of levothyroxine, and therefore should be noted while prescribing the medication. Pregnancy causes increased demands for thyroid hormones to support the proper development of the fetus. Therefore, prompt treatment of hypothyroidism is recommended.

Primary care physicians should utilize any of the screening guidelines along with maintaining good clinical judgment based on history, physical exam, and laboratory values. Following the initiation of medication, serum TSH levels should be measured 6–8 weeks later to ensure adequate treatment.

Conflict of interest

The authors declare no conflict of interest.