Diagnosis and Treatment of Hypothyroidism

Hypothyroidism is a condition in which the level of thyroid hormones circulating in the blood decreases due to various reasons. According to various studies, hypothyroidism is diagnosed in 0.1 to 2% (1–5) of the population, while subclinical hypothyroidism affects 4 to 10% of the population, more frequently in women than men (1, 2, 6, 7).

Based on the pathophysiological mechanisms, hypothyroidism is classified into:

• primary – due to decreased hormone synthesis in the thyroid gland. It is characterized by an increased concentration of thyroid-stimulating hormone (TSH) when the free thyroxine (FT4) concentration is below the lower limit of the norm. The most common cause worldwide is iodine deficiency (8), but in regions where there is sufficient iodine, it is more commonly caused by autoimmune thyroiditis (9);
• secondary (or central) – due to pituitary or hypothalamic pathology leading to a decrease in thyroid-stimulating hormones. In studies, the FT4 concentration is below the lower limit of the norm, while TSH does not adequately increase;
• subclinical – TSH concentration increases, while FT4 remains within the normal range.

It is important to determine whether hypothyroidism is primary or secondary, as this affects the treatment strategy, long-term monitoring approach, and, in some cases, the patient's prognosis.

When should hypothyroidism be suspected?

The symptoms of hypothyroidism are very diverse and can be characteristic of other diseases and conditions. The most common symptoms include fatigue, intolerance to cold, weight gain, constipation, dry skin, muscle pain, and, in women, irregular menstrual cycles. Other frequently occurring symptoms can be divided into several groups:

• skin symptoms. Upon examination of the patient, attention is first drawn to cool, pale, dry skin (10). Sometimes the skin may have a yellowish hue due to carotenemia. Sweating decreases. Hair thins, nails become brittle. In severe cases, myxedema due to the infiltration of the skin with glycosaminoglycans and water accumulation is observed (11). Periorbital edema may be present;
• laboratory blood changes. A complete blood count reveals normocytic normochromic anemia (12). Vitamin B12 deficiency anemia is diagnosed in 10% of patients with chronic autoimmune thyroiditis, while some patients without anemia may have elevated erythrocytes (13). Biochemical blood test changes can vary. Primary hypothyroidism is characterized by increased TSH concentration and FT4 concentration below the lower limit of the norm. Secondary (central) hypothyroidism is characterized by FT4 concentration below the lower limit of the norm and TSH concentration not adequately increased. Subclinical hypothyroidism is characterized by increased TSH and normal FT4 concentration (8). Hyponatremia may be detected due to water retention. Creatinine concentration in the blood is often elevated, and dyslipidemia is common. Clearance of certain medications may be impaired;
• cardiovascular system. Due to the slowdown in cellular metabolism in the absence of thyroid hormones, cardiac function is significantly affected. With a decrease in heart rate and the strength of contractions, cardiac output decreases (14, 15), leading to reduced tolerance to physical exertion and the onset of shortness of breath during mild physical activity. If the patient had a pre-existing heart condition, hypothyroidism can exacerbate it. In rare cases, fluid may be found in the pericardial cavity. Increased peripheral vascular resistance leads to elevated blood pressure. If the patient did not have primary arterial hypertension before, this change will be minor. Due to the slowdown in cholesterol metabolism, an increased concentration of cholesterol is detected in the blood (16, 17);
• respiratory function is also impaired, with changes occurring from the upper to the lower respiratory tract. Patients may experience rhinitis, shortness of breath, and difficulty exhaling. Respiratory muscle weakness can lead to hypoventilation and reduced response to hypoxia and hypercapnia (18–20). Tongue enlargement due to fluid retention affects sleep and may lead to sleep apnea (21);
• digestive disorders. Due to slowed bowel movements, patients often complain of constipation, and in rare cases, intestinal obstruction may occur (22). Taste receptors may also be affected. Weight gain may occur due to a slowed metabolism;
• reproductive dysfunction. In women, the menstrual cycle may be disrupted, leading to oligo- or amenorrhea or, conversely, hypermenorrhea and menorrhagia (23). These issues may result in infertility, and if a woman becomes pregnant, there is a high risk of early miscarriage (24). Hyperprolactinemia may also occur, often sufficient to cause amenorrhea and galactorrhea (25);
• neurological symptoms. Both the central and peripheral nervous systems may be affected, but these impairments are usually reversible with appropriate treatment. A common finding is carpal tunnel syndrome. In cases of severe hypothyroidism, myxedema coma may occur.

Diagnosis of Hypothyroidism

When hypothyroidism is suspected, the first test to be performed should be the determination of TSH levels in the blood. If the levels are within the normal range, further testing of the patient is unnecessary.

If TSH levels are elevated, a blood test should be done to determine the level of FT4 to assess the severity of hypothyroidism. If FT4 levels are low, replacement therapy with levothyroxine should be initiated.

If FT4 levels are within the normal range, the TSH test should be repeated after 2–3 months, and if it remains elevated, a diagnosis of subclinical hypothyroidism is made.

If central hypothyroidism is suspected (caused by pituitary or hypothalamic disease) or if clear hypothyroidism symptoms are present despite normal TSH levels, both TSH and FT4 levels should be evaluated.

Testing for antithyroid peroxidase antibodies (TPOAb) confirms the autoimmune origin of hypothyroidism, and in cases of subclinical hypothyroidism, this is a prognostic factor, as the presence of antibodies indicates a high likelihood of the disease progressing to clinically significant hypothyroidism.

Principles of Hypothyroidism Treatment

Levothyroxine is prescribed for the treatment of hypothyroidism. The benefit of treatment with a combination of levothyroxine and liothyronine remains unclear.

The dosage of levothyroxine is determined based on the severity of hypothyroidism, the patient's age, cardiovascular system status, and other conditions. Specific dosing considerations apply to women during pregnancy.

Treatment for hypothyroidism should start slowly and with lower doses in more severe cases. Typically, in adults without severe comorbidities, treatment starts with 25–50 μg once daily, with the dose increased by 25–50 μg every 2–4 weeks until the adequate replacement dose is reached, achieving euthyroidism (6, 28).

For patients with cardiovascular comorbidities, it is recommended to start with lower levothyroxine doses – 12.5 μg, increasing by 12.5 μg every 4 weeks until the adequate replacement dose is reached (28).

For patients over 50–60 years old, the initial dose is recommended to be 25 μg, gradually increasing every 4–6 weeks until the adequate replacement dose is reached.

The optimal individual levothyroxine dose is determined by assessing the patient's well-being and aiming to maintain a normal TSH level in the blood. The maintenance dose usually ranges from 1.5 to 2.0 μg/kg of body weight per day, i.e., from 50 μg to >200 μg per day (6).

Pregnant women should receive levothyroxine treatment when the blood serum TSH concentration exceeds the trimester-specific normal range and FT4 concentration is decreased, and when TSH concentration exceeds 10.0 mIU/l regardless of FT4 concentration in the blood. Treatment is recommended to start with moderate levothyroxine doses (e.g., 50 μg/day), gradually titrating the dose until the target TSH value specific to the trimester of pregnancy is achieved.

It is not recommended to use other thyroid hormone preparations, e.g., liothyronine.

The goal of treatment is to normalize the clinical condition and TSH concentration in the blood serum according to the specific reference ranges for each trimester of pregnancy (target TSH in the first trimester – 0.1–2.5 mIU/l, second trimester – 0.2–3.0 mIU/l, third trimester – 0.3–3.0 mIU/l).

It is recommended to evaluate TSH and FT4 concentrations approximately every 4 weeks up to weeks 16–20 of pregnancy, and at least once during weeks 26–32 (29).

The effect of levothyroxine greatly depends on proper administration. The optimal therapeutic effect is achieved when the medication is taken on an empty stomach. The recommended daily dose should be taken first thing in the morning on an empty stomach, 30 minutes before breakfast, with a small amount of water.

There are cases where the patient cannot fast in the morning (due to personal behavior traits or concomitant diseases). In such cases, it is recommended to take the prescribed levothyroxine dose all at once before bedtime, at least 2 hours after the last meal.

It should be noted that various medications (proton pump inhibitors, bile acid sequestrants, calcium carbonate, iron salts) or food products (e.g., coffee) impair the absorption of levothyroxine. Higher doses may be needed if the patient suffers from stomach and intestinal diseases that interfere with the absorption of levothyroxine.

There are different strengths of levothyroxine tablets available (e.g., L-Thyroxine 50 μg, L-Thyroxine 75 μg, L-Thyroxine 100 μg, and L-Thyroxine 125 μg), allowing the appropriate dose to be selected so that patients usually need to take only one tablet once daily

When starting levothyroxine, symptoms of hypothyroidism often improve after a few weeks, but it may take up to 6 weeks, or even longer in individual cases, for TSH levels to normalize. Therefore, repeating the TSH test is recommended after 6 weeks. If it remains elevated, the levothyroxine dose is increased by 12.5–25 μg per day, and then the TSH test is repeated after 6 weeks (28).

The goal of treatment is to maintain TSH levels within the normal range and normalize clinical symptoms, while also reducing thyroid enlargement in patients with autoimmune thyroiditis. Once TSH levels are normalized, the test should be repeated annually.

It is important to remember that thyroid hormone deficiency in pregnant women is harmful to the fetus, so thyroid function is monitored more closely in these patients, with pregnancy-specific reference ranges applied.

In cases of subclinical hypothyroidism, levothyroxine treatment is prescribed to all patients when TSH is >10 mU/l.

Summary

Hypothyroidism is one of the most common thyroid disorders. Left untreated, it significantly disrupts the functioning of the entire body and worsens quality of life. Since the symptoms of hypothyroidism are often characteristic of other medical conditions, every physician examining a patient should also consider this pathology.