User login
A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).
One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.
His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) was less than 0.70, and his FEV1 was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.
Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.
Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.
The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.
He was a retired engineer. He did not drink alcohol or use illicit drugs.
PHYSICAL EXAMINATION
On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m2.
His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.
Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.
His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.
Results of initial laboratory testing are shown in Table 1.
Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.
INITIAL MANAGEMENT
The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.
The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.
Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:
- pH 7.35
- Partial pressure of carbon dioxide (Paco2) 52 mm Hg
- Bicarbonate 28 mmol/L
- Partial pressure of oxygen (Pao2) 60 mm Hg
- Oxygen saturation 90%.
HOSPITAL COURSE
On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.
At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.
Because of these episodes, the attending physician ordered thyroid function tests.
THYROID FUNCTION TESTING
1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?
- Serum thyroid-stimulating hormone (TSH) alone
- Serum TSH and total thyroxine (T4)
- Serum TSH and total triiodothyronine (T3)
- Serum TSH and free T4
- Serum TSH and free T3
There are several tests to assess thyroid function: the serum TSH, total T4, free T4, total T3, and free T3 concentrations.1
In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T4 and T3, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T4 and TSH levels.2 Thus, the serum free T4 level can remain within the normal reference range even if the TSH level is high or low.
TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.3
TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.4 Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.4
Free vs total T4 and T3 levels
Serum total T4 includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T3. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.8 Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T4 and T3 levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T4, is usually recommended.
Although equilibrium dialysis is the method most likely to provide an accurate serum free T4 measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T4 measurement or, to a lesser degree, the free T4 index.9 However, none of the currently available free T4 tests actually measure free T4 directly; rather, they estimate it.10
Commercial laboratories can provide a direct free T3 estimate, but it may be less reliable than total T3. If serum T3 measurement is indicated, serum total T3 is usually measured. However, total T3 measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.11 Nevertheless, serum total T3 measurement could be useful in patients with T3 toxicosis and in those who are acutely ill.
Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T4 is essential to assess thyroid function. Many clinicians also measure serum total T3.
CASE CONTINUED: LOW TSH, LOW-NORMAL FREE T4, LOW TOTAL T3
The attending physician ordered serum TSH, free T4, and total T3 measurements, which yielded the following:
- TSH 0.1 mU/L (0.5–5.0)
- Total T3 55 ng/dL (80–180)
- Free T4 0.9 ng/dL (0.9–2.4).
2. Which best explains this patient’s abnormal thyroid test results?
- His acute illness
- Central hypothyroidism due to pituitary infarction
- His albuterol therapy
- Subclinical thyrotoxicosis
- Hashimoto thyroiditis
Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.1 In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.
Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T3, normal or low serum TSH, and normal, low, or high serum free T4. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.16 These abnormalities with their mechanisms are shown in Table 2.5–7 In several commercial kits, serum direct free T4 can be falsely decreased or increased.8
THE DIFFERENTIAL DIAGNOSIS
Our patient had low serum TSH, low-normal serum direct free T4, and low serum total T3. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.17 The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.
In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.18 Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.19,20
The serum concentration of reverse T3 has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.21
GLUCOCORTICOIDS AND THYROID FUNCTION TESTS
By inhibiting D1, glucocorticoids can decrease peripheral conversion of T4 to T3 and thus decrease serum total T3. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.
In one study,22 there was a significant reduction in serum total T3 concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T3 returned to its pretreatment level.
In another study,23 a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T3 in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.
Long-term glucocorticoid therapy also decreases serum total T4 and total T3 by lowering serum thyroid-binding globulin.24
Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.27
Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.28 Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T4 clearance.29
BETA-BLOCKERS, BETA-AGONISTS AND THYROID FUNCTION
While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.30
In studies of propranolol, serum total T4 concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients31–33; serum total T3 concentrations did not change or were decreased with 40 mg or more daily34; and serum reverse T3 concentrations were increased with daily doses of 80 mg or more.31 It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.
Furthermore, a significant decrease in serum total T3 concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).35,36
On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.37
SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?
Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.
The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.
Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T4 and total T3 remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).38,39
Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.40 Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.
CASE CONTINUED
An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.
3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?
- Start levothyroxine (T4) therapy
- Start liothyronine (T3) therapy
- Start N-acetylcysteine therapy
- Start thyrotropin-releasing hormone therapy
- Remeasure thyroid hormones after full recovery from his acute illness
It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.41
However, current data argue against thyroid hormone therapy using T4 or T3 for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).42 Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.41,43
Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.
Some studies showed that giving N-acetylcysteine, an antioxidant, increased serum T3 and decreased serum reverse T3 concentrations in patients with acute myocardial infarction.44 Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.
Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T4, and T3 levels in critically ill patients.45 The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.46
Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.47
CASE CONTINUED
The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.
Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.
One week later, his laboratory results were:
- TSH 11.2 mU/L (reference range 0.5–5.0)
- Free T4 1.2 ng/dL (0.9–2.4)
- Total T3 92 ng/dL (80–180).
Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.
4. Based on these last test results, which statement is correct?
- Levothyroxine therapy should be started
- His serum TSH elevation is most likely transient
- Thyroid ultrasonography is strongly indicated
- A radioactive iodine uptake study should be performed
- Measurement of thyroid-stimulating immunoglobulins is indicated
During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).48 Normalization of the thyroid function tests including serum TSH may take several weeks49 or months.50 However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.51
Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.
Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)
Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.52 Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.
CASE CONCLUSION: BETTER, BUT STILL SMOKING
The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T4, and total T3 were within normal ranges. His COPD was under control, with an FEV1 88% of predicted.
He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.
KEY POINTS
- In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
- If thyroid function assessment is indicated for critically ill patients, serum TSH and free T4 concentrations should be measured. Some clinicians also measure serum total T3 level.
- Thyroid function testing in critically ill patients usually shows low serum total T3, normal or low serum TSH, and normal or low serum free T4.
- Many drugs can alter thyroid hormone levels.
- Thyroid hormone therapy is not recommended for critically ill patients with low T3, low T4, or both.
- During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
- Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
- Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.
- Lamb EJ, Martin J. Thyroid function tests: often justified in the acutely ill. Ann Clin Biochem 2000; 37(pt 2):158–164. doi:10.1258/0004563001899159
- Spencer CA, LoPresti JS, Patel A, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990; 70(2):453–460. doi:10.1210/jcem-70-2-453
- Ross DS, Ardisson LJ, Meskell MJ. Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a new chemiluminescent assay. J Clin Endocrinol Metab 1989; 69(3):684–688. doi:10.1210/jcem-69-3-684
- Koulouri O, Moran C, Halsall D, Chatterjee K, Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab 2013; 27(6):745–762. doi:10.1016/j.beem.2013.10.003
- Lechan RM, Fekete C. Role of thyroid hormone deiodination in the hypothalamus. Thyroid 2005; 15(8):883–897. doi:10.1089/thy.2005.15.883
- Chopra IJ, Hershman JM, Pardridge WM, Nicoloff JT. Thyroid function in nonthyroidal ilnesses. Ann Intern Med 1983; 98(6):946–957. doi:10.7326/0003-4819-98-6-946
- Chopra IJ, Solomon DH, Hepner HW, Mortenstein AA. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann Intern Med 1979; 90(6):905–912. doi:10.7326/0003-4819-90-6-905
- Pontecorvi A, Robbins J. The plasma membrane and thyroid hormone entry into cells. Trends Endocrinol Metab 1989; 1(2):90–94. pmid:18411097
- Hennemann G, Krenning EP. Pitfalls in the interpretation of thyroid function tests in old age and non-thyroidal illness. Horm Res 1987; 26(1–4):100–104. doi:10.1159/000180688
- Baloch Z, Carayon P, Conte-Devolx B, et al; Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13(1):3–126. doi:10.1089/105072503321086962
- Lum S, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest 1984; 73(2):570–575. doi:10.1172/JCI111245
- Ortiga-Carvalho TM, Chiamolera MI, Pazos-Moura CC, Wondisford FE. Hypothalamus-pituitary-thyroid axis. Compr Physiol 2016; 6(3):1387–1428. doi:10.1002/cphy.c150027
- de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol 2015; 225(3):R67–R81. doi:10.1530/JOE-15-0133
- Chopra IJ, Huang TS, Beredo A, Solomon DH, Teco GN, Mean JF. Evidence for an inhibitor of extrathyroidal conversion of thyroxine to 3, 5, 3'-triiodothyronine in sera of patients with nonthyroidal illnesses. J Clin Endocrinol Metab 1985; 60(4):666–672. doi:10.1210/jcem-60-4-666
- Peeters RP, Debaveye Y, Fliers E, Visser TJ. Changes within the thyroid axis during critical illness. Crit Care Clin 2006; 22(1):41–55. doi:10.1016/j.ccc.2005.08.006
- Spencer C, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem 1987; 33(8):1391–1396. pmid:3301067
- Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am 2007; 36(3):657–672. doi:10.1016/j.ecl.2007.04.007
- Persani L. Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab 2012; 97(9):3068–3078. doi:10.1210/jc.2012-1616
- Kidess AI, Caplan RH, Reynertson RH, Wickus GG, Goodnough DE. Transient corticotropin deficiency in critical illness. Mayo Clin Proc 1993; 68(5):435–441. doi:10.1016/s0025-6196(12)60188-8
- Lamberts SW, Bruining HA, De Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997; 337(18):1285–1292. doi:10.1056/NEJM199710303371807
- Burmeister LA. Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome. Thyroid 1995; 5(6):435–441. doi:10.1089/thy.1995.5.435
- Duick DS, Warren DW, Nicoloff JT, Otis CL, Croxson MS. Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab 1974; 39(6):1151–1154. doi:10.1210/jcem-39-6-1151
- Gamstedt A, Järnerot G, Kågedal B. Dose related effects of betamethasone on iodothyronines and thyroid hormone-binding proteins in serum. Acta Endocrinol (Copenh) 1981; 96(4):484–490. doi:10.1530/acta.0.0960484
- Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the “euthyroid sick syndrome.” Endocr Rev 1982; 3(2):164–217. doi:10.1210/edrv-3-2-164
- Wilber JF, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969; 48(11):2096–2103. doi:10.1172/JCI106176
- Nicoloff JT, Fisher DA, Appleman MD Jr. The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest 1970; 49(10):1922–1929. doi:10.1172/JCI106411
- Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333(25):1688–1694. doi:10.1056/NEJM199512213332507
- Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab 2009; 23(6):793–800. doi:10.1016/j.beem.2009.08.003
- Sherman SI, Gopal J, Haugen BR, et al. Central hypothyroidism associated with retinoid X receptor–selective ligands. N Engl J Med 1999; 340(14):1075–1079. doi:10.1056/NEJM199904083401404
- Murchison LE, How J, Bewsher PD. Comparison of propranolol and metoprolol in the management of hyperthyroidism. Br J Clin Pharmacol 1979; 8(6):581–587. doi:10.1111/j.1365-2125.1979.tb01048.x
- Faber J, Friis T, Kirkegaard C, et al. Serum T4, T3 and reverse T3 during treatment with propranolol in hyperthyroidism, L-T4 treated myxedema and in normal man. Horm Metab Res 1979; 11(1):34–36. doi:10.1055/s-0028-1092678
- Kristensen BO, Weeke J. Propranolol-induced increments in total and free serum thyroxine in patients with essential hypertension. Clin Pharmacol Ther 1977; 22(6):864–867. doi:10.1002/cpt1977226864
- Murchison LE, Bewsher PD, Chesters MI, Ferrier WR. Comparison of propranolol and practolol in the management of hyperthyroidism. Br J Clin Pharmacol 1976; 3(2):273–277. doi:10.1111/j.1365-2125.1976.tb00603.x
- Lotti G, Delitala G, Devilla L, Alagna S, Masala A. Reduction of plasma triiodothyronine (T3) induced by propranolol. Clin Endocrinol 1977; 6(6):405–410. doi:10.1111/j.1365-2265.1977.tb03322.x
- Perrild H, Hansen JM, Skovsted L, Christensen LK. Different effects of propranolol, alprenolol, sotalol, atenolol and metoprolol on serum T3 and serum rT3 in hyperthyroidism. Clin Endocrinol (Oxf) 1983; 18(2):139–142. pmid:6133659
- Reeves RA, From GL, Paul W, Leenen FH. Nadolol, propranolol, and thyroid hormones: evidence for a membrane-stabilizing action of propranolol. Clin Pharmacol Ther 1985; 37(2):157–161. doi:10.1038/clpt.1985.28
- Walker N, Jung RT, Jennings G, James WP. The effect of a beta-receptor agonist (salbutamol) on peripheral thyroid metabolism in euthyroid subjects. Horm Metab Res 1981; 13(10):590–591. doi:10.1055/s-2007-1019346
- Melmed S, Geola FL, Reed AW, Pekary AE, Park J, Hershman JM. A comparison of methods for assessing thyroid function in nonthyroidal illness. J Clin Endocrinol Metab 1982; 54(2):300–306. doi:10.1210/jcem-54-2-300
- Docter R, Krenning E, De Jong M, Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993; 39(5):499–518. pmid:8252737
- Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990; 71(3):661–669. doi:10.1210/jcem-71-3-661
- De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies. Crit Care Clin 2006; 22(1):57–86. doi:10.1016/j.ccc.2005.10.001
- Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014; 24(12):1670–1751. doi:10.1089/thy.2014.0028
- Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab 2009; 94(10):3663–3675. doi:10.1210/jc.2009-0899
- Vidart J, Wajner SM, Leite RS, et al. N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial. J Clin Endocrinol Metab 2014; 99(12):4537–4545. doi:10.1210/jc.2014-2192
- Van den Berghe G, Wouters P, Weekers F, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab 1999; 84(4):1311–1323. doi:10.1210/jcem.84.4.5636
- Langouche L, Vander Perre S, Marques M, et al. Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab 2013; 98(3):1006–1013. doi:10.1210/jc.2012-2809
- Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A. Thyroid function during critical illness. Hormones (Athens) 2011; 10(2):117–124. doi:10.14310/horm.2002.1301
- Hamblin PS, Dyer SA, Mohr VS, et al. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab 1986; 62(4):717–722. doi:10.1210/jcem-62-4-717
- Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. Eur J Endocrinol 2009; 160(4):503–515. doi:10.1530/EJE-08-0837
- Spencer CA. Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients. Mayo Clin Proc 1988; 63(12):1214–1222. doi:10.1016/s0025-6196(12)65408-1
- Attia J, Margetts P, Guyatt G. Diagnosis of thyroid disease in hospitalized patients: a systematic review. Arch Intern Med 1999; 159(7):658–665. pmid:10218744
- Barbesino G, Tomer Y. Clinical review: clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab 2013; 98(6):2247–2255. doi:10.1210/jc.2012-4309
A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).
One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.
His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) was less than 0.70, and his FEV1 was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.
Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.
Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.
The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.
He was a retired engineer. He did not drink alcohol or use illicit drugs.
PHYSICAL EXAMINATION
On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m2.
His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.
Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.
His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.
Results of initial laboratory testing are shown in Table 1.
Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.
INITIAL MANAGEMENT
The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.
The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.
Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:
- pH 7.35
- Partial pressure of carbon dioxide (Paco2) 52 mm Hg
- Bicarbonate 28 mmol/L
- Partial pressure of oxygen (Pao2) 60 mm Hg
- Oxygen saturation 90%.
HOSPITAL COURSE
On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.
At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.
Because of these episodes, the attending physician ordered thyroid function tests.
THYROID FUNCTION TESTING
1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?
- Serum thyroid-stimulating hormone (TSH) alone
- Serum TSH and total thyroxine (T4)
- Serum TSH and total triiodothyronine (T3)
- Serum TSH and free T4
- Serum TSH and free T3
There are several tests to assess thyroid function: the serum TSH, total T4, free T4, total T3, and free T3 concentrations.1
In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T4 and T3, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T4 and TSH levels.2 Thus, the serum free T4 level can remain within the normal reference range even if the TSH level is high or low.
TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.3
TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.4 Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.4
Free vs total T4 and T3 levels
Serum total T4 includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T3. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.8 Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T4 and T3 levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T4, is usually recommended.
Although equilibrium dialysis is the method most likely to provide an accurate serum free T4 measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T4 measurement or, to a lesser degree, the free T4 index.9 However, none of the currently available free T4 tests actually measure free T4 directly; rather, they estimate it.10
Commercial laboratories can provide a direct free T3 estimate, but it may be less reliable than total T3. If serum T3 measurement is indicated, serum total T3 is usually measured. However, total T3 measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.11 Nevertheless, serum total T3 measurement could be useful in patients with T3 toxicosis and in those who are acutely ill.
Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T4 is essential to assess thyroid function. Many clinicians also measure serum total T3.
CASE CONTINUED: LOW TSH, LOW-NORMAL FREE T4, LOW TOTAL T3
The attending physician ordered serum TSH, free T4, and total T3 measurements, which yielded the following:
- TSH 0.1 mU/L (0.5–5.0)
- Total T3 55 ng/dL (80–180)
- Free T4 0.9 ng/dL (0.9–2.4).
2. Which best explains this patient’s abnormal thyroid test results?
- His acute illness
- Central hypothyroidism due to pituitary infarction
- His albuterol therapy
- Subclinical thyrotoxicosis
- Hashimoto thyroiditis
Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.1 In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.
Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T3, normal or low serum TSH, and normal, low, or high serum free T4. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.16 These abnormalities with their mechanisms are shown in Table 2.5–7 In several commercial kits, serum direct free T4 can be falsely decreased or increased.8
THE DIFFERENTIAL DIAGNOSIS
Our patient had low serum TSH, low-normal serum direct free T4, and low serum total T3. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.17 The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.
In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.18 Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.19,20
The serum concentration of reverse T3 has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.21
GLUCOCORTICOIDS AND THYROID FUNCTION TESTS
By inhibiting D1, glucocorticoids can decrease peripheral conversion of T4 to T3 and thus decrease serum total T3. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.
In one study,22 there was a significant reduction in serum total T3 concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T3 returned to its pretreatment level.
In another study,23 a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T3 in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.
Long-term glucocorticoid therapy also decreases serum total T4 and total T3 by lowering serum thyroid-binding globulin.24
Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.27
Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.28 Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T4 clearance.29
BETA-BLOCKERS, BETA-AGONISTS AND THYROID FUNCTION
While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.30
In studies of propranolol, serum total T4 concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients31–33; serum total T3 concentrations did not change or were decreased with 40 mg or more daily34; and serum reverse T3 concentrations were increased with daily doses of 80 mg or more.31 It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.
Furthermore, a significant decrease in serum total T3 concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).35,36
On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.37
SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?
Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.
The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.
Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T4 and total T3 remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).38,39
Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.40 Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.
CASE CONTINUED
An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.
3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?
- Start levothyroxine (T4) therapy
- Start liothyronine (T3) therapy
- Start N-acetylcysteine therapy
- Start thyrotropin-releasing hormone therapy
- Remeasure thyroid hormones after full recovery from his acute illness
It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.41
However, current data argue against thyroid hormone therapy using T4 or T3 for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).42 Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.41,43
Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.
Some studies showed that giving N-acetylcysteine, an antioxidant, increased serum T3 and decreased serum reverse T3 concentrations in patients with acute myocardial infarction.44 Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.
Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T4, and T3 levels in critically ill patients.45 The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.46
Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.47
CASE CONTINUED
The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.
Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.
One week later, his laboratory results were:
- TSH 11.2 mU/L (reference range 0.5–5.0)
- Free T4 1.2 ng/dL (0.9–2.4)
- Total T3 92 ng/dL (80–180).
Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.
4. Based on these last test results, which statement is correct?
- Levothyroxine therapy should be started
- His serum TSH elevation is most likely transient
- Thyroid ultrasonography is strongly indicated
- A radioactive iodine uptake study should be performed
- Measurement of thyroid-stimulating immunoglobulins is indicated
During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).48 Normalization of the thyroid function tests including serum TSH may take several weeks49 or months.50 However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.51
Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.
Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)
Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.52 Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.
CASE CONCLUSION: BETTER, BUT STILL SMOKING
The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T4, and total T3 were within normal ranges. His COPD was under control, with an FEV1 88% of predicted.
He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.
KEY POINTS
- In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
- If thyroid function assessment is indicated for critically ill patients, serum TSH and free T4 concentrations should be measured. Some clinicians also measure serum total T3 level.
- Thyroid function testing in critically ill patients usually shows low serum total T3, normal or low serum TSH, and normal or low serum free T4.
- Many drugs can alter thyroid hormone levels.
- Thyroid hormone therapy is not recommended for critically ill patients with low T3, low T4, or both.
- During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
- Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
- Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.
A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).
One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.
His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) was less than 0.70, and his FEV1 was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.
Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.
Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.
The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.
He was a retired engineer. He did not drink alcohol or use illicit drugs.
PHYSICAL EXAMINATION
On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m2.
His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.
Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.
His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.
Results of initial laboratory testing are shown in Table 1.
Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.
INITIAL MANAGEMENT
The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.
The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.
Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:
- pH 7.35
- Partial pressure of carbon dioxide (Paco2) 52 mm Hg
- Bicarbonate 28 mmol/L
- Partial pressure of oxygen (Pao2) 60 mm Hg
- Oxygen saturation 90%.
HOSPITAL COURSE
On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.
At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.
Because of these episodes, the attending physician ordered thyroid function tests.
THYROID FUNCTION TESTING
1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?
- Serum thyroid-stimulating hormone (TSH) alone
- Serum TSH and total thyroxine (T4)
- Serum TSH and total triiodothyronine (T3)
- Serum TSH and free T4
- Serum TSH and free T3
There are several tests to assess thyroid function: the serum TSH, total T4, free T4, total T3, and free T3 concentrations.1
In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T4 and T3, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T4 and TSH levels.2 Thus, the serum free T4 level can remain within the normal reference range even if the TSH level is high or low.
TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.3
TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.4 Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.4
Free vs total T4 and T3 levels
Serum total T4 includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T3. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.8 Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T4 and T3 levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T4, is usually recommended.
Although equilibrium dialysis is the method most likely to provide an accurate serum free T4 measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T4 measurement or, to a lesser degree, the free T4 index.9 However, none of the currently available free T4 tests actually measure free T4 directly; rather, they estimate it.10
Commercial laboratories can provide a direct free T3 estimate, but it may be less reliable than total T3. If serum T3 measurement is indicated, serum total T3 is usually measured. However, total T3 measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.11 Nevertheless, serum total T3 measurement could be useful in patients with T3 toxicosis and in those who are acutely ill.
Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T4 is essential to assess thyroid function. Many clinicians also measure serum total T3.
CASE CONTINUED: LOW TSH, LOW-NORMAL FREE T4, LOW TOTAL T3
The attending physician ordered serum TSH, free T4, and total T3 measurements, which yielded the following:
- TSH 0.1 mU/L (0.5–5.0)
- Total T3 55 ng/dL (80–180)
- Free T4 0.9 ng/dL (0.9–2.4).
2. Which best explains this patient’s abnormal thyroid test results?
- His acute illness
- Central hypothyroidism due to pituitary infarction
- His albuterol therapy
- Subclinical thyrotoxicosis
- Hashimoto thyroiditis
Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.1 In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.
Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T3, normal or low serum TSH, and normal, low, or high serum free T4. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.16 These abnormalities with their mechanisms are shown in Table 2.5–7 In several commercial kits, serum direct free T4 can be falsely decreased or increased.8
THE DIFFERENTIAL DIAGNOSIS
Our patient had low serum TSH, low-normal serum direct free T4, and low serum total T3. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.17 The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.
In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.18 Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.19,20
The serum concentration of reverse T3 has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.21
GLUCOCORTICOIDS AND THYROID FUNCTION TESTS
By inhibiting D1, glucocorticoids can decrease peripheral conversion of T4 to T3 and thus decrease serum total T3. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.
In one study,22 there was a significant reduction in serum total T3 concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T3 returned to its pretreatment level.
In another study,23 a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T3 in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.
Long-term glucocorticoid therapy also decreases serum total T4 and total T3 by lowering serum thyroid-binding globulin.24
Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.27
Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.28 Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T4 clearance.29
BETA-BLOCKERS, BETA-AGONISTS AND THYROID FUNCTION
While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.30
In studies of propranolol, serum total T4 concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients31–33; serum total T3 concentrations did not change or were decreased with 40 mg or more daily34; and serum reverse T3 concentrations were increased with daily doses of 80 mg or more.31 It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.
Furthermore, a significant decrease in serum total T3 concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).35,36
On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.37
SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?
Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.
The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.
Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T4 and total T3 remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).38,39
Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.40 Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.
CASE CONTINUED
An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.
3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?
- Start levothyroxine (T4) therapy
- Start liothyronine (T3) therapy
- Start N-acetylcysteine therapy
- Start thyrotropin-releasing hormone therapy
- Remeasure thyroid hormones after full recovery from his acute illness
It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.41
However, current data argue against thyroid hormone therapy using T4 or T3 for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).42 Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.41,43
Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.
Some studies showed that giving N-acetylcysteine, an antioxidant, increased serum T3 and decreased serum reverse T3 concentrations in patients with acute myocardial infarction.44 Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.
Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T4, and T3 levels in critically ill patients.45 The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.46
Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.47
CASE CONTINUED
The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.
Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.
One week later, his laboratory results were:
- TSH 11.2 mU/L (reference range 0.5–5.0)
- Free T4 1.2 ng/dL (0.9–2.4)
- Total T3 92 ng/dL (80–180).
Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.
4. Based on these last test results, which statement is correct?
- Levothyroxine therapy should be started
- His serum TSH elevation is most likely transient
- Thyroid ultrasonography is strongly indicated
- A radioactive iodine uptake study should be performed
- Measurement of thyroid-stimulating immunoglobulins is indicated
During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).48 Normalization of the thyroid function tests including serum TSH may take several weeks49 or months.50 However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.51
Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.
Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)
Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.52 Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.
CASE CONCLUSION: BETTER, BUT STILL SMOKING
The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T4, and total T3 were within normal ranges. His COPD was under control, with an FEV1 88% of predicted.
He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.
KEY POINTS
- In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
- If thyroid function assessment is indicated for critically ill patients, serum TSH and free T4 concentrations should be measured. Some clinicians also measure serum total T3 level.
- Thyroid function testing in critically ill patients usually shows low serum total T3, normal or low serum TSH, and normal or low serum free T4.
- Many drugs can alter thyroid hormone levels.
- Thyroid hormone therapy is not recommended for critically ill patients with low T3, low T4, or both.
- During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
- Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
- Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.
- Lamb EJ, Martin J. Thyroid function tests: often justified in the acutely ill. Ann Clin Biochem 2000; 37(pt 2):158–164. doi:10.1258/0004563001899159
- Spencer CA, LoPresti JS, Patel A, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990; 70(2):453–460. doi:10.1210/jcem-70-2-453
- Ross DS, Ardisson LJ, Meskell MJ. Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a new chemiluminescent assay. J Clin Endocrinol Metab 1989; 69(3):684–688. doi:10.1210/jcem-69-3-684
- Koulouri O, Moran C, Halsall D, Chatterjee K, Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab 2013; 27(6):745–762. doi:10.1016/j.beem.2013.10.003
- Lechan RM, Fekete C. Role of thyroid hormone deiodination in the hypothalamus. Thyroid 2005; 15(8):883–897. doi:10.1089/thy.2005.15.883
- Chopra IJ, Hershman JM, Pardridge WM, Nicoloff JT. Thyroid function in nonthyroidal ilnesses. Ann Intern Med 1983; 98(6):946–957. doi:10.7326/0003-4819-98-6-946
- Chopra IJ, Solomon DH, Hepner HW, Mortenstein AA. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann Intern Med 1979; 90(6):905–912. doi:10.7326/0003-4819-90-6-905
- Pontecorvi A, Robbins J. The plasma membrane and thyroid hormone entry into cells. Trends Endocrinol Metab 1989; 1(2):90–94. pmid:18411097
- Hennemann G, Krenning EP. Pitfalls in the interpretation of thyroid function tests in old age and non-thyroidal illness. Horm Res 1987; 26(1–4):100–104. doi:10.1159/000180688
- Baloch Z, Carayon P, Conte-Devolx B, et al; Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13(1):3–126. doi:10.1089/105072503321086962
- Lum S, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest 1984; 73(2):570–575. doi:10.1172/JCI111245
- Ortiga-Carvalho TM, Chiamolera MI, Pazos-Moura CC, Wondisford FE. Hypothalamus-pituitary-thyroid axis. Compr Physiol 2016; 6(3):1387–1428. doi:10.1002/cphy.c150027
- de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol 2015; 225(3):R67–R81. doi:10.1530/JOE-15-0133
- Chopra IJ, Huang TS, Beredo A, Solomon DH, Teco GN, Mean JF. Evidence for an inhibitor of extrathyroidal conversion of thyroxine to 3, 5, 3'-triiodothyronine in sera of patients with nonthyroidal illnesses. J Clin Endocrinol Metab 1985; 60(4):666–672. doi:10.1210/jcem-60-4-666
- Peeters RP, Debaveye Y, Fliers E, Visser TJ. Changes within the thyroid axis during critical illness. Crit Care Clin 2006; 22(1):41–55. doi:10.1016/j.ccc.2005.08.006
- Spencer C, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem 1987; 33(8):1391–1396. pmid:3301067
- Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am 2007; 36(3):657–672. doi:10.1016/j.ecl.2007.04.007
- Persani L. Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab 2012; 97(9):3068–3078. doi:10.1210/jc.2012-1616
- Kidess AI, Caplan RH, Reynertson RH, Wickus GG, Goodnough DE. Transient corticotropin deficiency in critical illness. Mayo Clin Proc 1993; 68(5):435–441. doi:10.1016/s0025-6196(12)60188-8
- Lamberts SW, Bruining HA, De Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997; 337(18):1285–1292. doi:10.1056/NEJM199710303371807
- Burmeister LA. Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome. Thyroid 1995; 5(6):435–441. doi:10.1089/thy.1995.5.435
- Duick DS, Warren DW, Nicoloff JT, Otis CL, Croxson MS. Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab 1974; 39(6):1151–1154. doi:10.1210/jcem-39-6-1151
- Gamstedt A, Järnerot G, Kågedal B. Dose related effects of betamethasone on iodothyronines and thyroid hormone-binding proteins in serum. Acta Endocrinol (Copenh) 1981; 96(4):484–490. doi:10.1530/acta.0.0960484
- Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the “euthyroid sick syndrome.” Endocr Rev 1982; 3(2):164–217. doi:10.1210/edrv-3-2-164
- Wilber JF, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969; 48(11):2096–2103. doi:10.1172/JCI106176
- Nicoloff JT, Fisher DA, Appleman MD Jr. The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest 1970; 49(10):1922–1929. doi:10.1172/JCI106411
- Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333(25):1688–1694. doi:10.1056/NEJM199512213332507
- Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab 2009; 23(6):793–800. doi:10.1016/j.beem.2009.08.003
- Sherman SI, Gopal J, Haugen BR, et al. Central hypothyroidism associated with retinoid X receptor–selective ligands. N Engl J Med 1999; 340(14):1075–1079. doi:10.1056/NEJM199904083401404
- Murchison LE, How J, Bewsher PD. Comparison of propranolol and metoprolol in the management of hyperthyroidism. Br J Clin Pharmacol 1979; 8(6):581–587. doi:10.1111/j.1365-2125.1979.tb01048.x
- Faber J, Friis T, Kirkegaard C, et al. Serum T4, T3 and reverse T3 during treatment with propranolol in hyperthyroidism, L-T4 treated myxedema and in normal man. Horm Metab Res 1979; 11(1):34–36. doi:10.1055/s-0028-1092678
- Kristensen BO, Weeke J. Propranolol-induced increments in total and free serum thyroxine in patients with essential hypertension. Clin Pharmacol Ther 1977; 22(6):864–867. doi:10.1002/cpt1977226864
- Murchison LE, Bewsher PD, Chesters MI, Ferrier WR. Comparison of propranolol and practolol in the management of hyperthyroidism. Br J Clin Pharmacol 1976; 3(2):273–277. doi:10.1111/j.1365-2125.1976.tb00603.x
- Lotti G, Delitala G, Devilla L, Alagna S, Masala A. Reduction of plasma triiodothyronine (T3) induced by propranolol. Clin Endocrinol 1977; 6(6):405–410. doi:10.1111/j.1365-2265.1977.tb03322.x
- Perrild H, Hansen JM, Skovsted L, Christensen LK. Different effects of propranolol, alprenolol, sotalol, atenolol and metoprolol on serum T3 and serum rT3 in hyperthyroidism. Clin Endocrinol (Oxf) 1983; 18(2):139–142. pmid:6133659
- Reeves RA, From GL, Paul W, Leenen FH. Nadolol, propranolol, and thyroid hormones: evidence for a membrane-stabilizing action of propranolol. Clin Pharmacol Ther 1985; 37(2):157–161. doi:10.1038/clpt.1985.28
- Walker N, Jung RT, Jennings G, James WP. The effect of a beta-receptor agonist (salbutamol) on peripheral thyroid metabolism in euthyroid subjects. Horm Metab Res 1981; 13(10):590–591. doi:10.1055/s-2007-1019346
- Melmed S, Geola FL, Reed AW, Pekary AE, Park J, Hershman JM. A comparison of methods for assessing thyroid function in nonthyroidal illness. J Clin Endocrinol Metab 1982; 54(2):300–306. doi:10.1210/jcem-54-2-300
- Docter R, Krenning E, De Jong M, Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993; 39(5):499–518. pmid:8252737
- Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990; 71(3):661–669. doi:10.1210/jcem-71-3-661
- De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies. Crit Care Clin 2006; 22(1):57–86. doi:10.1016/j.ccc.2005.10.001
- Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014; 24(12):1670–1751. doi:10.1089/thy.2014.0028
- Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab 2009; 94(10):3663–3675. doi:10.1210/jc.2009-0899
- Vidart J, Wajner SM, Leite RS, et al. N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial. J Clin Endocrinol Metab 2014; 99(12):4537–4545. doi:10.1210/jc.2014-2192
- Van den Berghe G, Wouters P, Weekers F, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab 1999; 84(4):1311–1323. doi:10.1210/jcem.84.4.5636
- Langouche L, Vander Perre S, Marques M, et al. Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab 2013; 98(3):1006–1013. doi:10.1210/jc.2012-2809
- Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A. Thyroid function during critical illness. Hormones (Athens) 2011; 10(2):117–124. doi:10.14310/horm.2002.1301
- Hamblin PS, Dyer SA, Mohr VS, et al. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab 1986; 62(4):717–722. doi:10.1210/jcem-62-4-717
- Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. Eur J Endocrinol 2009; 160(4):503–515. doi:10.1530/EJE-08-0837
- Spencer CA. Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients. Mayo Clin Proc 1988; 63(12):1214–1222. doi:10.1016/s0025-6196(12)65408-1
- Attia J, Margetts P, Guyatt G. Diagnosis of thyroid disease in hospitalized patients: a systematic review. Arch Intern Med 1999; 159(7):658–665. pmid:10218744
- Barbesino G, Tomer Y. Clinical review: clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab 2013; 98(6):2247–2255. doi:10.1210/jc.2012-4309
- Lamb EJ, Martin J. Thyroid function tests: often justified in the acutely ill. Ann Clin Biochem 2000; 37(pt 2):158–164. doi:10.1258/0004563001899159
- Spencer CA, LoPresti JS, Patel A, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990; 70(2):453–460. doi:10.1210/jcem-70-2-453
- Ross DS, Ardisson LJ, Meskell MJ. Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a new chemiluminescent assay. J Clin Endocrinol Metab 1989; 69(3):684–688. doi:10.1210/jcem-69-3-684
- Koulouri O, Moran C, Halsall D, Chatterjee K, Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab 2013; 27(6):745–762. doi:10.1016/j.beem.2013.10.003
- Lechan RM, Fekete C. Role of thyroid hormone deiodination in the hypothalamus. Thyroid 2005; 15(8):883–897. doi:10.1089/thy.2005.15.883
- Chopra IJ, Hershman JM, Pardridge WM, Nicoloff JT. Thyroid function in nonthyroidal ilnesses. Ann Intern Med 1983; 98(6):946–957. doi:10.7326/0003-4819-98-6-946
- Chopra IJ, Solomon DH, Hepner HW, Mortenstein AA. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann Intern Med 1979; 90(6):905–912. doi:10.7326/0003-4819-90-6-905
- Pontecorvi A, Robbins J. The plasma membrane and thyroid hormone entry into cells. Trends Endocrinol Metab 1989; 1(2):90–94. pmid:18411097
- Hennemann G, Krenning EP. Pitfalls in the interpretation of thyroid function tests in old age and non-thyroidal illness. Horm Res 1987; 26(1–4):100–104. doi:10.1159/000180688
- Baloch Z, Carayon P, Conte-Devolx B, et al; Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13(1):3–126. doi:10.1089/105072503321086962
- Lum S, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest 1984; 73(2):570–575. doi:10.1172/JCI111245
- Ortiga-Carvalho TM, Chiamolera MI, Pazos-Moura CC, Wondisford FE. Hypothalamus-pituitary-thyroid axis. Compr Physiol 2016; 6(3):1387–1428. doi:10.1002/cphy.c150027
- de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol 2015; 225(3):R67–R81. doi:10.1530/JOE-15-0133
- Chopra IJ, Huang TS, Beredo A, Solomon DH, Teco GN, Mean JF. Evidence for an inhibitor of extrathyroidal conversion of thyroxine to 3, 5, 3'-triiodothyronine in sera of patients with nonthyroidal illnesses. J Clin Endocrinol Metab 1985; 60(4):666–672. doi:10.1210/jcem-60-4-666
- Peeters RP, Debaveye Y, Fliers E, Visser TJ. Changes within the thyroid axis during critical illness. Crit Care Clin 2006; 22(1):41–55. doi:10.1016/j.ccc.2005.08.006
- Spencer C, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem 1987; 33(8):1391–1396. pmid:3301067
- Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am 2007; 36(3):657–672. doi:10.1016/j.ecl.2007.04.007
- Persani L. Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab 2012; 97(9):3068–3078. doi:10.1210/jc.2012-1616
- Kidess AI, Caplan RH, Reynertson RH, Wickus GG, Goodnough DE. Transient corticotropin deficiency in critical illness. Mayo Clin Proc 1993; 68(5):435–441. doi:10.1016/s0025-6196(12)60188-8
- Lamberts SW, Bruining HA, De Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997; 337(18):1285–1292. doi:10.1056/NEJM199710303371807
- Burmeister LA. Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome. Thyroid 1995; 5(6):435–441. doi:10.1089/thy.1995.5.435
- Duick DS, Warren DW, Nicoloff JT, Otis CL, Croxson MS. Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab 1974; 39(6):1151–1154. doi:10.1210/jcem-39-6-1151
- Gamstedt A, Järnerot G, Kågedal B. Dose related effects of betamethasone on iodothyronines and thyroid hormone-binding proteins in serum. Acta Endocrinol (Copenh) 1981; 96(4):484–490. doi:10.1530/acta.0.0960484
- Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the “euthyroid sick syndrome.” Endocr Rev 1982; 3(2):164–217. doi:10.1210/edrv-3-2-164
- Wilber JF, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969; 48(11):2096–2103. doi:10.1172/JCI106176
- Nicoloff JT, Fisher DA, Appleman MD Jr. The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest 1970; 49(10):1922–1929. doi:10.1172/JCI106411
- Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333(25):1688–1694. doi:10.1056/NEJM199512213332507
- Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab 2009; 23(6):793–800. doi:10.1016/j.beem.2009.08.003
- Sherman SI, Gopal J, Haugen BR, et al. Central hypothyroidism associated with retinoid X receptor–selective ligands. N Engl J Med 1999; 340(14):1075–1079. doi:10.1056/NEJM199904083401404
- Murchison LE, How J, Bewsher PD. Comparison of propranolol and metoprolol in the management of hyperthyroidism. Br J Clin Pharmacol 1979; 8(6):581–587. doi:10.1111/j.1365-2125.1979.tb01048.x
- Faber J, Friis T, Kirkegaard C, et al. Serum T4, T3 and reverse T3 during treatment with propranolol in hyperthyroidism, L-T4 treated myxedema and in normal man. Horm Metab Res 1979; 11(1):34–36. doi:10.1055/s-0028-1092678
- Kristensen BO, Weeke J. Propranolol-induced increments in total and free serum thyroxine in patients with essential hypertension. Clin Pharmacol Ther 1977; 22(6):864–867. doi:10.1002/cpt1977226864
- Murchison LE, Bewsher PD, Chesters MI, Ferrier WR. Comparison of propranolol and practolol in the management of hyperthyroidism. Br J Clin Pharmacol 1976; 3(2):273–277. doi:10.1111/j.1365-2125.1976.tb00603.x
- Lotti G, Delitala G, Devilla L, Alagna S, Masala A. Reduction of plasma triiodothyronine (T3) induced by propranolol. Clin Endocrinol 1977; 6(6):405–410. doi:10.1111/j.1365-2265.1977.tb03322.x
- Perrild H, Hansen JM, Skovsted L, Christensen LK. Different effects of propranolol, alprenolol, sotalol, atenolol and metoprolol on serum T3 and serum rT3 in hyperthyroidism. Clin Endocrinol (Oxf) 1983; 18(2):139–142. pmid:6133659
- Reeves RA, From GL, Paul W, Leenen FH. Nadolol, propranolol, and thyroid hormones: evidence for a membrane-stabilizing action of propranolol. Clin Pharmacol Ther 1985; 37(2):157–161. doi:10.1038/clpt.1985.28
- Walker N, Jung RT, Jennings G, James WP. The effect of a beta-receptor agonist (salbutamol) on peripheral thyroid metabolism in euthyroid subjects. Horm Metab Res 1981; 13(10):590–591. doi:10.1055/s-2007-1019346
- Melmed S, Geola FL, Reed AW, Pekary AE, Park J, Hershman JM. A comparison of methods for assessing thyroid function in nonthyroidal illness. J Clin Endocrinol Metab 1982; 54(2):300–306. doi:10.1210/jcem-54-2-300
- Docter R, Krenning E, De Jong M, Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993; 39(5):499–518. pmid:8252737
- Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990; 71(3):661–669. doi:10.1210/jcem-71-3-661
- De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies. Crit Care Clin 2006; 22(1):57–86. doi:10.1016/j.ccc.2005.10.001
- Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014; 24(12):1670–1751. doi:10.1089/thy.2014.0028
- Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab 2009; 94(10):3663–3675. doi:10.1210/jc.2009-0899
- Vidart J, Wajner SM, Leite RS, et al. N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial. J Clin Endocrinol Metab 2014; 99(12):4537–4545. doi:10.1210/jc.2014-2192
- Van den Berghe G, Wouters P, Weekers F, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab 1999; 84(4):1311–1323. doi:10.1210/jcem.84.4.5636
- Langouche L, Vander Perre S, Marques M, et al. Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab 2013; 98(3):1006–1013. doi:10.1210/jc.2012-2809
- Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A. Thyroid function during critical illness. Hormones (Athens) 2011; 10(2):117–124. doi:10.14310/horm.2002.1301
- Hamblin PS, Dyer SA, Mohr VS, et al. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab 1986; 62(4):717–722. doi:10.1210/jcem-62-4-717
- Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. Eur J Endocrinol 2009; 160(4):503–515. doi:10.1530/EJE-08-0837
- Spencer CA. Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients. Mayo Clin Proc 1988; 63(12):1214–1222. doi:10.1016/s0025-6196(12)65408-1
- Attia J, Margetts P, Guyatt G. Diagnosis of thyroid disease in hospitalized patients: a systematic review. Arch Intern Med 1999; 159(7):658–665. pmid:10218744
- Barbesino G, Tomer Y. Clinical review: clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab 2013; 98(6):2247–2255. doi:10.1210/jc.2012-4309
