creation date: 2025-05-01 18:56
tags: Pathologies
Hypothyroidism
Background
Definitions
Hypothyroidism is characterized by a low level of thyroid hormone.
Primary hypothyroidism: thyroid gland cannot produce adequate thyroid hormone (TSH elevated by feedback)
Secondary hypothyroidism: abnormal pituitary gland (under secreting TSH)
Tertiary hypothyroidism: abnormal hypothalamus
Secondary and tertiary hypothyroidism is referred together as central hypothyroidism.
Subclinical hypothyroidism: mildly elevated TSH with normal levels of T3 and T4
Etiology
In primary hypothyroidism, the most common cause is Hashimoto thyroiditis which is an autoimmune process. In iodine-deficient areas, iodine deficiency is the most prevalent cause.
Other causes of primary hypothyroidism includes:
- Postpartum thyroiditis
- Riedel’s disease (fibrosing thyroiditis)
- Painless lymphocytic thyroiditis
- Use of radioactive iodine for Graves disease
- Subacute granulomatous thyroiditis (post-viral URTI)
- Autoimmune polyendocrinopathy
- Iatrogenic
- Thyroid surgery
- Radiation to head/neck
- Immune checkpoint inhibitors
- Medications including amiodarone, thalidomide, lithium etc.
Causes of central hypothyroidism include:
- Neoplastic, infiltrative, inflammatory, genetic, or iatrogenic disorders of pituitary or hypothalamus
- Pituitary tumours
- Tumours compressing hypothalamus
- Sheehan syndrome (damage to to pituitary due to blood loss during childbirth)
- TRH resistance or deficiency
- Lymphocytic hypophysitis
- Radiation therapy to brain
- Medications such as dopamine, prednisone, or opioids
Pathogenesis
The secretion of thyroid hormone involves the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates thyroid-stimulating hormone (TSH) from the anterior pituitary gland which stimulates T4 and some T3. T4 is converted to T3 peripherally.
While the pathophysiology varies depending on etiology, they generally are due to some impairment of a component of the axis and thus downstream production of thyroid hormone.
In Hashimoto’s thyroiditis, anti-TPO autoantibodies target TPO which is crucial for thyroid hormone production. The inflammation results in turnover of iodine and impaired organification.
With many forms of thyroiditis, inflammation results in an initial transient hyperthyroid phase. Following the depletion of the stored hormones, the destruction due to thyroiditis results in impaired ability to synthesize more thyroid hormone resulting in permanent hypothyroidism.
In iodine deficiency, the lack of iodine impairs production of thyroid hormone as iodine is a part of the molecular structure of the hormone.
Low levels of thyroid hormone results in impaired glycoaminosglycan synthesis in fibrosis leading to accumulation in tissue and dermis. This draws water and manifests as myxedema.
Clinical Presentation
Signs & Symptoms
The manifestations of hypothyroidism reflect the downstream effects of a lack of thyroid hormones:
- Slowing of metabolic processes
- Accumulation of matrix glycoaminoglycans in interstitial spaces of tissue
Organized by organ system, symptoms include:
Skin
- Cool and pale (decreased blood flow)
- Dry roughness (atrophied layer of epidermis and hyperkeratosis)
- Decreased sweating
- Skin discolouration (carotenemia or hyperpigmentation)
- Coarse hair and hair loss
- Brittle nails
- Nonpitting edema (myxedema)
Eyes - Periorbital edema
Hematologic - Increased bleeding risk (acquired von Willebrand’s syndrome type 1)
- Decreased red blood cell mass and normochromic, normocytic hypoproliferative anemia or iron deficiency anemia secondary to menorrhagia
Cardiovascular - Decrease in cardiac output (decreased heart rate and contractility)
- Decreased exercise capacity
- Pericardial effusion
- Hypertension (due to increase in peripheral vascular resistance)
- Hypercholesterolemia (decreased rate of cholesterol metabolism)
- Hyperhomocysteinemia
Respiratory - Hypoventilation from respiratory muscle weakness
- Impaired respiratory function resulting in fatigue, shortness of breath on exertion, rhinitis, and decreased exercise capacity
Gastrointestinal - Decreased gut motility resulting in constipation
- Decreased taste sensation
- Gastric atrophy
- Celiac disease
- Metabolic dysfunction-associated steatotic liver disease
- Weight gain
- Ascities (rarely)
Reproductive - Oligo- or amenorrhea or hypermenorrhea-menorrhagia
- Menstrual changes result in decreased fertility
- Hyperprolactinemia
- Decreased libido, erectile dysfunction, and delayed ejaculation
Neurologic - Hashimoto encephalopathy: immune-mediated subacute onset of confusion, ALC, seizures, and myoclonus
- Myxedema coma: severe hypothyroidism complicated by trauma, infection, cold exposure, or inadvertent administration of hypnotics or opiates
- Carpal tunnel
Musculoskeletal - Weakness, cramps, and myalgias
- Joint pains, aches, and stiffness (less common)
Metabolic - Hyponatremia (due to reduced water clearance)
- Lipid abnormalities
- Reduced drug clearance
Additionally, patients who have been treated for Graves disease hyperthyroidism may have signs and symptoms associated with that while hypothyroidal.
History & Physical Exam
Clinical features should be elicited from a history. A high level of suspicion should be used as symptoms are often mild and nonspecific. Symptoms should initiate a hypothyroid work up such as:
- Fatigue
- Constipation
- Cold intolerance
- Weight gain
- Menstrual cycle abnormalities
A physical exam of the thyroid and other systems for signs and symptoms should be done. Physical exam may reveal thyroidectomy scar.
Risk factors
Risk factors include:
- Female sex (10:1)
- Advancing age
- White or Asian ethnicity
- Family history of thyroid disease
- Personal history of autoimmune disease
- Previous thyroid surgery or RAI therapy
- Radiation to the head or neck
Diagnosis
Criteria
Diagnosis is made using thyroid function tests.
Overt hypothyroidism
- High TSH
- Low free T4
Subclinical hypothyroidism - High TSH
- Normal free T4
Central hypothyroidism - Low TSH (or inappropriately low for the low T4)
- Low free T4
Work-up
With primary hypothyroidism, a detailed history should try to elicit alternative causes such as past treatment of hyperthyroidism, medications, or iodine deficiency.
In the case of no alternative cause, etiology can be assumed to be Hashimoto’s thyroiditis.
Additional testing is not usually required but in more ambiguous cases, a thyroid peroxidase (TPO) antibody assay can be done which would be elevated in autoimmune thyroiditis.
In cases of central hypothyroidism, neuroradiologic studies (eg. MRI) is required to assess the hypothalamic-pituitary region.
Differential
Other diagnoses of elevated serum TSH include:
- Resistance to TSH
- Resistance to thyroid hormone
- Recovery from nonthyroidal illness
- TSH-secreting pituitary adenomas
Red Flags / Complications
Severe hypothyroidism may present as myxedema coma which is an endocrine emergency. This presents as:
- Encephalopathy
- Hypothermia
- Seizures
- Hyponatremia
- Hypoglycemia
- Arrhythmias
- Cardiogenic shock
- Respiratory failure
- Fluid retention
and needs to be treated with IV hydrocortisone followed by IV levothyroxine.
Management
In most cases of hypothyroidism, lifelong treatment is required. In some cases treatment may be discontinued if hypothyroidism is transient (eg. with painless thyroiditis or subacute thyroiditis).
Hypothyroidism is corrected with synthetic thyroxine (T4):
- Levothyroxine (Synthroid) PO on empty stomach 30-60 min before breakfast or at bedtime at least 2 hours after last meal (due to calcium)
- Initial dose: full replacement dose is ~1.6mcg/kg per day
- In younger patient, full dose
- In older adults or those with coronary heart disease, start on lower dose (25-50 mcg/day) - due to increased myocardial oxygen demand caused by thyroid hormone
Symptoms typically improve within 2 weeks but complete recovery can take longer. If symptoms are persistent on evaluation after 2-3 weeks, the dose can be increased without additional testing. Note that values at this time may not be stabilized due to the 6 weeks (6 half-lives) needed for steady state.
Normal reference range for TSH is approximately 0.5-4.5 mU/L. For older adults, there is an age-related shift towards higher TSH levels. Typical target for treatment is <3 mU/L.
If TSH remains above the reference range:
- Ensure patient is taking medication as prescribed (not with calcium) and the same brand/generic is used (to avoid inter-brand variability)
- In younger patients, increase dose based on degree of TSH elevation
- In older adults or those with CHD, increase dose by 12-25 mcg/day
- Recheck TSH in 6 weeks
If TSH is within reference range, the dose is used for maintenance. TSH should be reassessed once yearly unless there is a change in patient status (eg. weight gain/loss, initiation of androgen therapy, pregnancy). The dose does not need to adjusted in asymptomatic patients with normal or slightly decreased TSH as normal fluctuation can occur.
For central hypothyroidism, treatment is generally the same except dosing is titrated to free T4 in the upper half of the reference range due to the unreliability of TSH in such cases.
Subclinical Hypothyroidism
With subclinical hypothyroidism, pharmacologic treatment is typically not necessary. Thyroid levels should be monitored.
Pharmacological treatment may be indicated if:
- Presence of comorbidities
- TSH level ≥10