Diagnóstico de hipotireoidismo em adultos.

Making the diagnosis:
Primary hypothyroidism(1):
- elevated thyroid-stimulating hormone (TSH), often > 10 milliunits/L
- decreased serum free thyroxine (FT4), or low-normal levels with symptoms of hypothyroidism
Subclinical hypothyroidism(1)
- elevated TSH, often 5-10 milliunits/L
- normal serum FT4
Secondary and tertiary hypothyroidism(1)
- serum TSH may be low, normal, or slightly elevated
- decreased serum FT4, or low-normal levels with symptoms of hypothyroidism
- impaired TSH response to TSH-releasing hormone (TRH) in secondary hypothyroidism (may be normal finding in men > 45 years old)
- frequently accompanied by other symptoms of hypothalamic or pituitary deficiency such as amenorrhea, galactorrhea, or erectile dysfunction
Myxedema coma is hypothyroidism presenting with(5)
- tupor, confusion, or coma
- hypothermia
- low serum total and FT4 and triiodothyronine (T3) concentrations

Differential diagnosis:
nonthyroidal illness syndrome(2)
- abnormalities in thyroid-stimulating hormone (TSH) or thyroid hormone levels in ill patients in the absence of underlying thyroid disease
- associated with acute, severe systemic illness
- most common pattern is low total and free triiodothyronine (T3) with normal TSH and thyroxine (T4)
- TSH level usually normal but may be low (rarely undetectable) or increased (transiently elevated during illness recovery)
- very sick patients with dramatic fall in T4 (low T4 syndrome) have poor prognosis
Other causes of similar symptoms
- anemia
- normal pregnancy (fatigue, constipation, fluid retention)
- adrenocortical insufficiency, especially in patients who have worsening symptoms despite thyroid hormone replacement (BMJ 2001 Aug 11;323(7308):332 full-text)
- liver failure (ascites, encephalopathy) mimicked hypothyroidism in patient with cirrhosis in case report (Ann Intern Med 2007 Feb 20;146(4):315)
Other causes of increased TSH levels
- recovery from severe illness(2)
- metoclopramide
- chlorpromazine
- haloperidol
- amiodarone
Testing overview:
- avoid routine testing of thyroid function in acutely ill patients(2)
- thyroid tests for initial diagnosis
- thyroid-stimulating hormone (TSH) as initial test in most patients
- free thyroxine (FT4) for confirmation of elevated TSH, or suspected pituitary or hypothalamic disease
- triiodothyronine (T3) not helpful (often normal even in severe hypothyroidism)(1)
- antithyroid peroxidase antibody (TPOAb) if autoimmune disease suspected(1)
- for ongoing monitoring of replacement therapy(1)
- TSH monitoring sufficient for primary hypothyroidism
- FT4 monitoring necessary in secondary and tertiary hypothyroidism
- typical monitoring frequency of TSH is every 3-6 months until stable, then annually unless, (return of clinical symptoms, pregnancy, estrogen use
large changes in body weight, advancing age).
- for monitoring of untreated subclinical hypothyroidism(4)
- if antithyroid peroxidase antibody-negative, repeat TSH in 3 years (2% progression per year)
- if antithyroid peroxidase antibody-positive, repeat TSH every year and monitor closely for clinical signs of hypothyroidism (nearly 5% progression per year)
- for suspected myxedema coma, check for adrenal insufficiency or pituitary disease (but initiate treatment with hydrocortisone while awaiting test results)(5)
- in hospitalized but not critically ill patients who are about to be treated with levothyroxine, consider possibility of adrenal insufficiency (ATA Strong recommendation, Low-quality evidence)
- patients with untreated adrenal insufficiency may have elevated TSH, but defer diagnosis of hypothyroidism until after starting treatment because -  - TSH may normalize with glucocorticoid replacement therapy(7)
Blood tests:
Thyroid-stimulating hormone (TSH):
American Thyroid Association guidelines for detection of thyroid dysfunction recommends
TSH as initial screening test in most cases
TSH plus free thyroxine (FT4) if suspected pituitary or hypothalamic disease
Reference - Arch Intern Med 2000 Jun 12;160(11):1573 PDF
thyroid-stimulating hormone (TSH) alone adequate for screening, normal TSH associated with very low likelihood of abnormal free thyroxine (FT4)
based on retrospective study of 1,392 paired results of sensitive TSH and FT4
1,340 results (96.2%) were concordant
47 discordant results (3.4%) had abnormal TSH and normal FT4
5 results (0.4%) had abnormal FT4 with normal TSH
Reference - Fam Med 2003 Jun;35(6):408
reference ranges for TSH
reference range of a given laboratory should determine upper limit of normal for third generation TSH assay (AACE/ATA Grade A, Level 1)(7)
normal TSH reference range changes with age
consider upper limit of normal of 4.12 milliunits/L if age-based upper limit of normal for third generation TSH assay is not available in iodine sufficient area
reference range for TSH in pregnancy should be trimester-specific (ATA Grade A)(6)
normal range should be based on trimester-specific ranges for that laboratory
if trimester-specific reference ranges for TSH are not available in the laboratory, recommended normal reference ranges
first trimester - 0.1-2.5 milliunits/L
second trimester - 0.2-3 milliunits/L
third trimester - 0.3-3 milliunits/L
TSH useful for diagnosis of hypothyroidism but does not correlate with severity of clinical symptoms (BMJ 2003 Feb 8;326(7384):311 full-text), editorial can be found in BMJ 2003 Feb 8;326(7384):295 full-text, commentary can be found in BMJ 2003 May 17;326(7398):1086 full-text
hypothyroidism with normal TSH may occur with
secondary or tertiary hypothyroidism(1)
dopamine(7)
steroids(7)
nonthyroidal illness(1, 2, 7)
TSH significantly decreased in first trimester pregnancy(5)
especially multiple gestation
nomograms adjusting for fetal number and gestational age derived from prospective TSH screening in 13,599 singleton and 132 twin pregnancies (Obstet Gynecol 2005 Oct;106(4):753), commentary can be found in Obstet Gynecol 2006 Jan;107(1):205
Thyroid hormone:
thyroxine (T4)
in serum, 99.97% of thyroxine is bound to protein (predominantly T4 binding globulin [TBG])(7)
free T4 is active, nonprotein-bound form (preferred over total T4)(7)
usually decreased in hypothyroidism(1, 7)
may be normal in subclinical hypothyroidism (TSH 5-10 milliunits/L)(1)
serum free T4 recommended instead of total T4 in evaluation of hypothyroidism (AACE/ATA Grade A, Level 1)(7)
free T4 preferred over total T4 because total T4 may be affected by changes in TBG concentration(7)
drugs or conditions that may increase TBG concentration include
pregnancy
neonatal period
estrogens (including oral contraceptives with estrogen) and selective estrogen receptor modulators (SERMs)
hepatitis
methadone
fluorouracil
mitotane
perphenazine
porphyria
congenital elevated TBG
drugs or conditions that may decrease TBG concentration include
congenital TBG deficiency
androgens
high-dose steroids
severe illness
nephrotic syndrome
cirrhosis
asparaginase
niacin
inhibitors of binding of TBG to T4 include
salicylates
furosemide
phenytoin
free fatty acids
heparin
carbamazepine
nonsteroidal anti-inflammatory drugs (NSAIDs)
for assessment of serum free T4(7)
in nonpregnant patients, assessment of serum free T4 includes free T4 index or free T4 estimate and direct immunoassay of free T4 without physical separation using anti-T4 antibody (AACE/ATA Grade A, Level 1)
in pregnancy (AACE/ATA Grade B, Level 2)
measure total T4 or free T4 index, in addition to TSH
direct immunoassay measurement of free T4 should only be used when method-specific and trimester-specific ranges for serum free T4 are available
in patients with central hypothyroidism, use free T4 or free T4 index, and not TSH, to diagnose and guide treatment of hypothyroidism (AACE/ATA Grade A, Level 1)
tri-iodothyronine (T3)
do not use serum total T3 or serum free T3 to diagnose hypothyroidism (AACE/ATA Grade A, Level 2)(7)
Endocrine Society and American Association of Clinical Endocrinologists recommend against ordering total or free T3 level when assessing levothyroxine (T4) dose in hypothyroid patients (Choosing Wisely)
significance of alterations in serum triiodothyronine levels within reference range, or of mildly low serum triiodothyronine levels, is unknown
Thyroid antibodies:
autoimmune thyroid disease may occur with elevated antithyroid antibody titers including(7)
antimicrosomal/thyroid peroxidase antibody (TPOAb)
TSH receptor antibodies (TSHRAbs) which may act as
TSH agonist - thyroid stimulating immunoglobulin (TSI)
TSH antagonist - thyrotropin binding inhibitory immunoglobulin (TBII)
antithyroglobulin antibody (TgAb)
TPOAb
TPOAb levels should be considered for(7)
evaluating patients with subclinical hypothyroidism (AACE/ATA Grade B, Level 1) - rate of developing hypothyroidism increases from 2.6%/year to 4.3%/year if positive TPOAb
identifying autoimmune thyroiditis when nodular thyroid disease is suspected to be due to autoimmune thyroid disease (AACE/ATA Grade D, Level 4)
evaluating patients with recurrent miscarriage, with or without infertility (AACE/ATA Grade A, Level 2)
TPOAb is preferred test for autoimmune thyroiditis
detectable in > 90% of cases of autoimmune thyroid disease
more specific and less expensive than antimicrosomal and antithyroglobulin antibody tests
Reference - Thyroid 2003 Jan;13(1):3
thyrotropin receptor autoantibodies (TSHRAbs)(7)
consider TSHRAbs using sensitive assay in hypothyroid pregnant patients with history of Graves disease who were treated with radioactive iodine or thyroidectomy prior to pregnancy (AACE/ATA Grade A, Level 2)
measure either at 20-26 weeks of gestation, or during first trimester and repeat at 20-26 weeks of gestation if elevated
strong correlation between high TSHRAbs titers and development of fetal or neonatal Graves disease
antithyroglobulin antibody detectable in about 70% of cases of autoimmune thyroid disease(1)
Other blood tests:
cardiac biomarkers
creatine kinase (CK) but not troponin T levels may be elevated in hypothyroidism
based on cohort of 25 patients with primary hypothyroidism
14 patients (56%) had elevated CK levels (up to 1,221 units/L)
4 patients (16%) had elevated CK-myoglobin (CK-MB) levels
all patients had normal cardiac troponin T levels
Reference - Intern Med J 2009 Feb;39(2):117
CK levels commonly elevated in patients with hypothyroidism
based on cohort of 28 patients with overt hypothyroidism, 38 patients with subclinical hypothyroidism, and 30 controls
elevated CK levels found in 16 patients (57%) with overt hypothyroidism and 4 (10.5%) with subclinical hypothyroidism
Reference - Endocr Res 2005;31(3):171
other possible lab findings in hypothyroidism
hypercholesterolemia(5)
anemia(5), may be
microcytic (due to reduced iron absorption from achlorhydria)
normocytic (due to decreased erythropoietin levels)
macrocytic (due to associated pernicious anemia)
increased lactate dehydrogenase (LDH)(5)
increased transaminases (serum alanine aminotransferase [ALT], serum aspartate aminotransferase [AST])
decreased sodium(1, 5)
hyperprolactinemia
false elevations of tumor markers
cancer antigen 19-9 (CA-19-9) tumor marker; case report of patient with hypothyroidism who had CA-19-9 level 36.5 units/mL (normal 0-22 units/mL) which returned to normal (16 units/mL) after adequate treatment of hypothyroidism (Mayo Clin Proc 2002 Apr;77(4):398)
cancer antigen 125 (CA-125) (BMJ 2002 Oct 26;325(7370):946 full-text)
cholesterol levels and muscles enzymes should not be used to diagnose hypothyroidism (AACE/ATA Grade B, Level 2)(7)
for assessment of secondary hypothyroidism, consider testing(1)
response to TSH-releasing hormone (TRH)
prolactin
adrenocorticotropic hormone (ACTH), and/or ACTH stimulation
gonadotropin levels in postmenopausal women and men (normal menstruation indicates normal gonadotropin secretion)
see also Hypopituitarism and Hypogonadism in males
tissue biomarkers of thyroid hormone action
tissue biomarkers of thyroid hormone action under investigation include sex hormone binding globulin (SHBG), osteocalcin, urinary N-telopeptides (NTX), total cholesterol, LDL cholesterol, lipoprotein(a), creatine kinase, ferritin, myoglobin, tissue plasminogen enzyme level, angiotensin-converting enzyme (ACE) enyzme level, and glucose 6-phosphate dehydrogenase enzyme level
tissue biomarkers of thyroid hormone action are not recommended for clinical use outside of research setting (ATA Weak recommendation, Low-quality evidence)
In patients with secondary hypothyroidism in whom the only available biochemical thyroid parameters are thyroid hormone levels, tissue markers of thyroid hormone action may be used as an adjunctive means of judging adequacy of levothyroxine replacement (ATA Weak recommendation, Low-quality evidence)
genetic testing (for type 2 deiodinase gene polymorphisms) not recommended for selecting patients for combination treatment with levothyroxine and liothyronine (ATA Strong recommendation, Moderate-quality evidence)
Imaging studies:
rarely needed for diagnosis
decreased 24-hour radioactive iodine uptake(7)
if defect in organification of iodine, short-term uptake may be increased
for secondary hypothyroidism, consider imaging of pituitary to rule out tumor or other lesion (see also Hypopituitarism)
Endocrine Society and American Association of Clinical Endocrinologists recommend against routine use of thyroid ultrasound in patients with abnormal thyroid function tests if there is no palpable abnormality of thyroid gland (Choosing Wisely)
Electrocardiography (ECG):
bradycardia, heart block, low voltage (especially with pericardial effusion)(1)
review of electrocardiogram findings can be found in BMJ 2002 Jun 1;324(7349):1320 full-text, correction can be found in BMJ 2002 Aug 3;325(7358):259, BMJ 2007 May 26;334(7603):1118
Other diagnostic testing:
In patients in whom levothyroxine dose requirements are much higher than expected, consider evaluation for gastrointestinal disorders such as Helicobacter pylori-related gastritis, atrophic gastritis, or celiac disease (ATA Strong recommendation, Moderate-quality evidence)
Fonte: Saúde baseada evidências. Dynamed.