Definition, Etiology, Pathogenesis Top
The clinical manifestations of hypothyroidism are caused by deficiency of thyroxine (T4) and the resulting insufficient cellular effects of triiodothyronine (T3), leading to a general slowing down of metabolic processes and to the development of interstitial edema due to deposition of fibronectin and hydrophilic glycosaminoglycans in the subcutaneous tissue, muscles, and other tissues.
The following types of hypothyroidism may be distinguished:
1) Primary hypothyroidism, which results from damage to the thyroid gland; it may be caused by:
a) Chronic autoimmune thyroiditis (most frequently Hashimoto thyroiditis), other types of thyroiditis.
b) Total or subtotal thyroidectomy (with a possible autoimmune process leading to the damage of the remaining thyroid parenchyma).
c) Treatment with 131I (radioiodine).
d) Irradiation of the neck.
e) Excessive intake of iodides, including the administration of amiodarone and iodine contrast media (by inhibiting iodide organification and T4 and T3 synthesis—known as the Wolff-Chaikoff effect—which could be transient or result in permanent hypothyroidism in cases of failure to escape the acute effect). Overdose of antithyroid drugs (transient and reversible hypothyroidism, improves upon discontinuation of the drug).
f) Administration of lithium salts (inhibition of T4 and T3 secretion), sodium nitroprusside, phenytoin, some tyrosine kinase inhibitors (eg, sunitinib, sorafenib), interferon alpha, or interleukin 2.
g) Significant environmental iodine deficiency and chronic exposure to goitrogens, that is, substances that inhibit the accumulation of iodides by the thyroid gland (eg, perchlorates, thiocyanates, nitrates).
h) Infiltrative diseases (eg, hemochromatosis, sarcoidosis).
i) Congenital hypothyroidism (eg, thyroid agenesis, dysgenesis, or defects in hormone synthesis).
2) Secondary hypothyroidism, which results from a decrease in or lack of thyroid-stimulating hormone (TSH) secretion due to hypopituitarism caused by:
a) Parasellar neoplasia.
b) Inflammatory or infiltrative conditions.
c) Vascular, traumatic, or iatrogenic injury (irradiation, neurosurgery procedures).
d) Hemorrhagic necrosis (Sheehan syndrome).
3) Tertiary hypothyroidism, resulting from a decrease in or lack of secretion of thyrotropin-releasing hormone (TRH), which is caused by damage to the hypothalamus (malignancy, sarcoidosis) or by a disrupted pituitary stalk.
Clinical Features and Natural History Top
In secondary and tertiary hypothyroidism, the signs and symptoms are usually less pronounced than in primary hypothyroidism, but there may be coexisting features of other endocrine deficiencies (look for the features of adrenal insufficiency, diabetes insipidus, or other symptoms directly related to hypopituitarism). Hypothyroidism can also be a part of polyglandular autoimmune syndromes.
In patients with subclinical hypothyroidism, typical signs and symptoms of hypothyroidism are absent; mood disorders and depression may be present along with abnormal laboratory test results, such as elevated serum total and low-density lipoprotein cholesterol (LDL-C) levels. The risk of developing clinically overt hypothyroidism increases 2-fold if an elevated TSH level is accompanied by high titers of thyroperoxidase (TPO) antibodies. The nonspecific symptoms of both subclinical and overt hypothyroidism may make the distinction difficult.
1. General signs and symptoms: Weight gain, fatigue, weakness and poor exercise tolerance, somnolence, general slowing down (affecting both psychomotor functions and speech), feeling cold, cold intolerance.
2. Cutaneous manifestations: Dry, cold, pale, and/or slightly yellowish skin; reduced perspiration, excessive epidermal keratosis, for instance, on the elbows; subcutaneous edema (so-called myxedema) with coarse facial features, typical edema of the eyelids and hands; coarse, brittle hair; loss of hair, sometimes including the eyebrows.
3. Cardiovascular manifestations: Bradycardia, hypokinetic pulse, distant heart sounds; enlarged cardiac silhouette; hypotension or, less commonly, hypertension (diastolic).
4. Respiratory manifestations: Hoarse and mellow voice (due to thickened vocal cords and an enlarged tongue); shallow breathing and a low respiratory rate; chronic signs and symptoms of upper respiratory tract congestion; in severe cases, symptoms of respiratory failure.
5. Gastrointestinal manifestations: Chronic constipation; ileus (in severe cases); ascites (in advanced disease; usually accompanied by pericardial and pleural effusion).
6. Urinary manifestations: Impaired water excretion (decreased renal filtration is important because of the risk of volume overload). In the absence of clinically overt edema, the abnormalities are probably insignificant.
7. Nervous system manifestations: Cognitive dysfunction, nerve entrapment syndromes (eg, carpal tunnel syndrome), paresthesias, hyporeflexia, a delayed relaxation phase of the deep tendon reflexes. Some patients may have hearing impairment.
8. Musculoskeletal manifestations: Muscle weakness and fatigue, loss of energy, lethargy, muscle cramps, myalgia; joint edema, particularly affecting the knees (due to synovial hypertrophy and effusion).
9. Reproductive system manifestations: In women, menstrual dysfunction (reduced cycle duration, menorrhagia), infertility, miscarriage, and galactorrhea; in men, loss of libido, sometimes also erectile dysfunction.
10. Psychiatric manifestations: Impaired concentration and memory, subclinical or overt depression, mood lability, sometimes symptoms of bipolar disorder or paranoid psychosis. In extremely severe cases, dementia and coma.
Myxedema coma is a life-threatening condition that develops in extremely severe untreated hypothyroidism; it may be triggered by comorbidity, for instance, by sepsis. Symptoms include hypothermia (body temperature <30 degrees Celsius, but it may be as low as 23 degrees Celsius), significant bradycardia, hypotension, hypoxemia and hypercapnia (caused by hypoventilation), hypoglycemia, hyponatremia with symptoms of volume overload, edema, cognitive dysfunction, coma, and shock. Patients may have reduced muscle tone (although they may develop seizures) and hyporeflexia. Signs and symptoms of comorbidities may be observed, for instance, pneumonia or other infections, acute myocardial infarction, or gastrointestinal bleeding.
1. Hormone tests:
1) Serum TSH concentrations: Elevated in primary hypothyroidism (the key diagnostic criterion), low or not appropriately elevated in secondary and tertiary hypothyroidism.
2) Low serum free thyroxine (FT4) levels.
3) Serum free triiodothyronine (FT3) levels may often be normal, or sometimes low.
4) The serum TSH level in the thyrotropin-releasing hormone test (now rarely used): In primary hypothyroidism, TSH hypersecretion. In secondary hypothyroidism, no significant TSH increase. In tertiary hypothyroidism, delayed, moderate elevation of TSH levels.
2. Other laboratory tests:
1) Elevated antithyroid antibody levels (primarily TPO antibodies) in an autoimmune thyroid disease.
2) Elevated levels of total cholesterol, LDL-C, and triglycerides.
4) Hyponatremia and mild hypercalcemia may be seen in some patients.
3. Imaging studies: Thyroid ultrasonography: features are variable and depend on the cause of hypothyroidism (the thyroid gland may be small, normal, or enlarged with heterogeneous appearance; foci of altered echogenicity may be seen). Abdominal ultrasonography: ascites in advanced disease. Chest radiography: in advanced disease, pleural effusion, an enlarged cardiac silhouette. Echocardiography: in advanced disease, pericardial effusion, left ventricular enlargement, reduced ejection fraction (due to impaired myocardial contractility). Radionuclide thyroid imaging: radioactive iodine uptake may be low or normal.
4. Electrocardiography (ECG): Sinus bradycardia, low amplitudes of ECG waveforms, particularly the QRS complex; flat or inverted T waves, a prolonged PR interval; rarely, third-degree atrioventricular block, a prolonged QT interval.
1. Primary hypothyroidism:
1) Overt: Low serum FT4 and elevated serum TSH levels.
2) Subclinical: Normal serum FT4 (often close to the lower limit of normal) with normal serum FT3 and mildly elevated serum TSH levels (typically <10 mIU/L).
2. Secondary and tertiary hypothyroidism: Low serum FT4 with normal or low serum TSH levels.
3. Myxedema coma: Low serum FT4 and usually markedly elevated serum TSH. The diagnosis depends primarily on clinical manifestations and exclusion of other causes of coma.
Differential diagnostic algorithm for hypothyroidism: Figure 1. When considering the differential diagnosis of primary hypothyroidism, look for a family history of thyroid diseases, exposure to iodine or chemical goitrogens, recent childbirth, treatment with antithyroid drugs, previous thyroid surgery, 131I therapy, or neck irradiation (including treatment completed several years earlier). Autoimmune hypothyroidism may be accompanied by insufficiency of other endocrine glands. In the case of secondary hypothyroidism, look for coexisting adrenal insufficiency before initiating hormone replacement therapy. Edema, effusions in body cavities, hypercholesterolemia, and anemia must be differentiated from nephrotic syndrome, pernicious anemia, and heart failure.
In patients hospitalized in an intensive care unit or recovering from a severe disease not related to the thyroid gland, the TSH level may be above the reference range but still remain <20 mIU/L. Certain medications used in the acute setting (eg, dopamine, dobutamine, glucocorticoids) decrease serum TSH levels. Predominantly as a result of impaired synthesis, the levels of thyroid hormone-binding proteins decrease in nonthyroidal illness, which leads to low serum total T3 and T4 levels. FT4 levels may also be found to be low, although methods for assessing FT4 are unreliable during severe illness. Reverse T3 (rT3) levels increase; the measurement of rT3 levels can be useful in distinguishing between nonthyroidal illness and central hypothyroidism (rT3 levels are low in central hypothyroidism) but is not commonly ordered. The term euthyroid sick syndrome is used to describe these laboratory abnormalities. Despite these abnormal findings, patients usually do not warrant thyroid hormone replacement therapy. In view of the abnormal results of hormone tests of the pituitary-thyroid axis observed in hospitalized patients with severe illness, thyroid function tests should be performed only if there is a strong suspicion of clinically relevant thyroid dysfunction.
Overt hypothyroidism is an absolute indication for hormone replacement therapy, usually lifelong.
Monotherapy with levothyroxine (L-T4) is the treatment of choice. Fixed combinations of L-T4 and liothyronine (L-T3) are not recommended, as T4 is converted to T3. Dosage: once daily, 30 to 60 minutes before the first meal or at bedtime 4 hours after the last meal. The daily dose is estimated on an individual basis: in adults usually ~1.7 microg/kg/d; in the elderly use lower doses, even as low as 1 microg/kg/d. In the majority of patients, the dose range is 100-150 microg/d (TSH levels should be within the reference range, optimally 2-3 mIU/L). In young, healthy adults, initiating treatment with full replacement doses is suggested.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to imprecision (a low number of events). Roos A, Linn-Rasker SP, van Domburg RT, Tijssen JP, Berghout A. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med. 2005 Aug 8-22;165(15):1714-20. Erratum in: Arch Intern Med. 2005 Oct 24;165(19):2227. PubMed PMID: 16087818. For patients older than 50 to 60 years without evidence of coronary heart disease, you may consider a low dose (50 microg/d) when initiating therapy, whereas among those with evidence of coronary heart disease, the usual starting dose is 12.5-25 microg/d. Dose adjustments are guided by measuring the TSH level 4 to 8 weeks following the initiation of L-T4. Once the therapeutic dose has been established, reevaluate TSH levels after 6 months, and later after 1 year and in the event new clinical manifestations are observed. Note that some drugs may reduce the absorption or metabolism of L-T4 (eg, calcium or iron supplements, bisphosphonates, sulfonylureas). Measure TSH levels within 4 to 8 weeks of introducing a new therapy. In regions with an adequate iodine intake, iodine products should not be used in the treatment of hypothyroidism, except in pregnant women.
In patients with low levels of thyroid hormones, serum cortisol half-life is prolonged and normalizes during L-T4 therapy; in the case of coexisting adrenal insufficiency, this may trigger symptoms of acute adrenal crisis. Therefore, in the case of coexisting hypothyroidism and adrenal insufficiency, always start treatment with cortisol replacement (see Primary Adrenal Insufficiency).
In subclinical hypothyroidism, L-T4 treatment is suggested in patients with serum TSH levels >10 mIU/L.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and the observational nature of data. Rodondi N, den Elzen WP, Bauer DC, et al; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010 Sep 22;304(12):1365-74. doi: 10.1001/jama.2010.1361. PubMed PMID: 20858880; PubMed Central PMCID: PMC3923470. If TSH levels are 5-10 mIU/L, treatment should likely be considered in patients with TPO antibodies, ischemic heart disease, heart failure, or risk factors for these conditions.
Treatment monitoring: Assess serum TSH levels no sooner than 3 weeks after the last L-T4 dose adjustment. In patients with secondary and tertiary hypothyroidism, measure the FT4 level (TSH is not useful in these cases).
Increasing the previously established hormone replacement dose (under TSH level monitoring) may be necessary in the following cases:
1) Oral L-T4 malabsorption (eg, in patients with inflammatory bowel diseases).
2) In patients requiring concomitant administration of drugs that cause L-T4 malabsorption (eg, cholestyramine, aluminum hydroxide, calcium and iron supplements), maintain a several-hour interval between the administration of L-T4 and these drugs.
3) Starting estrogen products (eg, oral contraceptives).
Myxedema coma is an endocrine emergency associated with a high mortality risk (>20%) that should be treated aggressively.
1. Intravenous L-T4; on day 1 administer 300 to 800 microg IV in a single infusion or using an infusion pump (to correct the L-T4 deficiency; this may result in an evident clinical improvement within several hours), and on subsequent days administer 50 to 100 microg IV once daily in a rapid infusion or using an infusion pump (take special care in patients with coronary heart disease due to the high risk of triggering angina, heart failure, or arrhythmia). When improvement is seen, switch to oral administration, usually 1.7 microg/kg/d or 100 to 150 microg/d (it is not necessary to start with a low dose of L-T4 and titrate it up). Alternatively, intravenous L-T4 and L-T3 may be used: on day 1 administer 200 to 400 microg IV L-T4 plus a separate T3 preparation (5-20 microg IV infusion); on subsequent days administer L-T4 50 to 100 microg/d IV plus L-T3 2.5 to 10 microg tid IV (use lower doses in the elderly and in patients at high risk of cardiovascular complications; continue intravenous L-T3 until clinical improvement is seen and the patient’s clinical condition is stable). If intravenous preparations are not available, oral combination containing 20 microg L-T3 and 100 microg L-T4 may be used: on day 1 administer 3 to 4 tablets once daily via a nasogastric tube; on subsequent days, 1 or 2 tablets via a nasogastric tube. When the patient’s condition improves, administer 1 tablet once daily or L-T4 100 to 150 microg/d. Note that oral treatment is less reliable than the intravenous route due to the possibility of malabsorption.
2. Ensure good ventilation: Intubation and ventilatory support are usually required.
3. Correct any electrolyte disturbances and hypoglycemia using intravenous fluids; do not use hypotonic fluids due to the risk of water intoxication. In case of severe dilutional hyponatremia and hypovolemia, consider a hypertonic NaCl infusion (see Hyponatremia). In euvolemic patients with hyponatremia, treatment is the same as in patients with syndrome of inappropriate antidiuretic hormone secretion.
4. Aggressively treat concomitant diseases, such as heart failure or infection (administer empiric antibiotic therapy until the culture and susceptibility results are available).
5. Until the possibility of concomitant adrenal insufficiency is excluded, use glucocorticoids in stress doses (eg, IV hydrocortisone 50-100 mg every 6 hours); they may be discontinued immediately after a normal serum cortisol level is confirmed in a sample collected before the administration of hydrocortisone.
6. Do not actively rewarm a hypothermic patient as this may cause vascular dilation and shock (a warm blanket is sufficient to prevent further heat loss).
Special Considerations Top
1. According to the 2012 Endocrine Society guidelines, screening for thyroid disorders before a planned pregnancy is indicated in women at high risk of thyroid diseases, which includes patients with thyroid disorders, after thyroidectomy, with a history of postpartum thyroiditis, with a family history of thyroid disease, with a goiter, with elevated plasma levels of thyroid antibodies, with signs or symptoms suggestive of thyroid disorders, with type 1 diabetes mellitus or other autoimmune disorders, with infertility, with a history of miscarriage or preterm delivery, and with prior therapeutic head or neck irradiation.
2. In pregnant women, the TSH level is usually measured in weeks 4 to 8 of pregnancy, during the first obstetric visit. According to the Endocrine Society, the maximum serum TSH level is 2.5 mIU/L before pregnancy and in the first trimester, and 3 mIU/L in the second and third trimesters.
3. Measure TPO antibody levels in:
1) Patients with a coexisting autoimmune disease (in particular type 1 diabetes mellitus) or a family history of such disorders.
2) Patients with a TSH level >2.5 mIU/L.
3) Patients in whom ultrasonography of the thyroid gland suggests autoimmune disease.
4) Patients with a positive history of postpartum thyroiditis.
5) Patients who are treated for infertility, have a history of miscarriage or preterm delivery. Significant correlations between elevated TPO antibodies and miscarriage, preterm delivery, and neonatal respiratory failure have been identified.
4. Supplementation with potassium iodide is not recommended in North America, although it is used in some geographic areas where access to iodine is of concern.
5. In pregnant patients with overt hypothyroidism, start L-T4 at a dose that covers the daily requirement. In patients diagnosed with hypothyroidism before pregnancy, increase the dose of L-T4 by 30% to 50%, usually in weeks 4 to 6 of pregnancy. In the majority of patients, the dose has to be reduced after delivery. In pregnant women with subclinical hypothyroidism, L-T4 is suggested.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Note: There is a disagreement among authors regarding the strength of this recommendation (strong vs weak). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and the nonrandomized nature of data. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab. 2010 Apr;95(4):1699-707. doi: 10.1210/jc.2009-2009. Epub 2010 Feb 3. PubMed PMID: 20130074. Reid SM, Middleton P, Cossich MC, Crowther CA, Bain E. Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev. 2013 May 31;5:CD007752. doi: 10.1002/14651858.CD007752.pub3. Review. PubMed PMID: 23728666. In the first half of pregnancy, monitor TSH levels (as well as T4 and FT4) every 4 weeks, and measure TSH levels at least once between weeks 26 and 32. Measuring FT4 levels does not always allow for an accurate evaluation of the thyroid status during pregnancy; in the second and third trimesters, the reference ranges are adapted by multiplying the total T4 (TT4) levels from before pregnancy by 1.5. However, due to the changing levels of T4-binding globulin, TT4 levels may be considered less accurate than FT4 levels.
Figure 1. Diagnostic algorithm of hypothyroidism based on TSH and FT4 levels.