hypothyroidism
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Etiology
- primary hypothyroidism > 90%
- chronic lymphocytic thyroiditis (Hashimoto's thyroiditis) is the most common cause of goitrous hypothyroidism
- iatrogenic due to thyroidectomy, radioiodine ablation or external beam radiation to the neck
- idiopathic primary hypothyroidism (possibly autoimmune block of TSH receptors [Graves disease variant])
- iodine deficiency
- postpartum thyroiditis (transient or more commonly permanent)
- subacute thyroiditis (generally transient, less commonly permanent)
- drugs
- iodides, lithium carbonate, interferon-alpha, interleukin-2, p-aminosalicylate, amiodarone
- tyrosine kinase inhibitors (TKIs)
- hypothyroidism as a result of cancer chemotherapy with TKIs is associated with increased survival[26]
- developmental
- biosynthetic defects
- agenesis of thyroid
- secondary hypothyroidism: uncommon
- pituitary insufficiency
- hypopituitarism
- pituitary adenoma
- empty sella syndrome
- pituitary irradiation
- pituitary surgery
- pituitary lesions usually occur in association with other evidence of pituitary disease
- hypothalamic (TRH) deficiency is rare
- pituitary insufficiency
- consider myxedema coma in severe cases
Epidemiology
- common, prevalence increases with age
- women > men.
- prevalence
- subclinical hypothyroidism (increased serum TSH, normal serum free T4 & serum free T3) is more common than overt clinical hypothyroidism (3.9% in general population)[5]
Pathology
- skeletal muscle: myopathy
- cardiac
- cardiac enlargement
- reduced myocardial contractility
- pericardial effusion in 1/3
- heart failure rare in absence of associated heart disease
- incidence coronary heart disease increased 2-fold
- pulmonary - obstructive sleep apnea & central sleep apnea
Clinical manifestations
- Symptoms:
- Signs:
- slow deep tendon reflex relaxation*
- no upper motor neuron signs
- myoedema (muscle mounding after percussion)
- myopathy, symmetric proximal muscle weakness
- bradycardia
- non-pitting edema
- myxedema, periorbital edema, weight gain
- may be reported as peripheral edema
- goiter
- galactorrhea when associated with hyperprolactinemia[3]
- low body temperature, generally not reaching criteria for hypothermia (< 35 C)
- cool dry skin
- carpal tunnel syndrome[32]
- difficulty with adducting thumb[32]
- Rarely:
- hypoventilation, pericardial & pleural effusion, deafness, arthralgias, arthritis, tibial collapse, osteonecrosis of the hip, epiphyseal dysgenesis, ataxia, distal symmetric polyneuropathy[3]
- Late manifestations:
- cardiomyopathy, facial & periorbital edema, thickened dry skin
- Elderly often present with non-specific signs/symptoms:
- anorexia, weakness, hearing loss, anemia, slow deep tendon reflex relaxation*
* may be only presenting sign in the elderly
Laboratory
- serum thyroid-stimulating hormone (TSH)*
- serum TSH > 20 uIU/mL confirms the diagnosis of primary hypothyroidism
- serum TSH 7-20 uIU/mL may occur in non thyroidal illness
- high serum TSH (< 20 uIU/mL) with normal serum free T4 occurs in subclinical hypothyroidism
- low serum TSH with low serum free T4 is associated with hypothyroidism secondary to pituitary-hypothalamic dysfunction
- monitoring serum TSH of no benefit if hypothyroidism is due to pituitary-hypothalamic dysfunction[3]
- no evidence to support routine screening with serum TSH[8]
- serum T4, free T4 index, serum free T4 & serum free T3 are low*
- serum free T4 should be used for evaluating hypothyroidism[15]
- serum TSH, serum total T4 & free thyroxine index should be used for evaluation of pregnant patients[15]
- neither serum T3 nor serum free T3 should be used for diagnosis of hypothyroidism[15]
- serum free T4 if hypothyroidism due to pituitary insufficiency
- basic metabolic panel: serum sodium: hyponatremia
- serum creatine kinase is increased
- tests for Hashimoto's thyroiditis
- thyroid peroxidase antibody in serum
- high levels predict permanent hypothyroidism
- thyroglobulin in serum
- diagnosis does not affect treatment
- vigilance for other autoimmune disorders if confirmed
- thyroid peroxidase antibody in serum
- evidence of hypoadrenalism if hypothyroidism is confirmed
- lipid panel:
- serum homocysteine: hyperhomocysteinemia
- complete blood count (CBC)
- serum prolactin may be elevated (< 200 ng/mL)
- not so for adequately treated hypothyroidism[3]
* initial diagnostic tests (serum free T3 not necessary)[3]
Diagnostic procedures
Radiology
- thyroid imaging (ultrasonography or thyroid scintigraphy) not indicated unless concern for thyroid nodule on exam[3]
- MRI not necessary for hyperprolactinemia when serum prolactin < 200 ng/mL[3] (image[29])
Complications
- peripheral neuropathy in treated hypothyroidism[14]
- hyperprolactinemia is commonly caused by hypothyroidism
- myxedema coma
- nephrotic syndrome may result in excessive urine thyroxine with subsequent hypothyroidism in patients on thyroxine- replacement therapy[19]
- primary thyroid lymphoma in elderly women with long-standing history of Hashimoto's thyroiditis[3]
- disease interaction(s) of hypothyroidism with adrenal insufficiency
- disease interaction(s) of hypothyroidism with nephrotic syndrome
Differential diagnosis
Management
- thyroxine (T4, levothyroxine, Synthroid, Levoxyl)
- begin thyroxine replacement when serum TSH > 10 uIU/mL[3]
- begin 50-100 ug/day
- 1.6 ug/kg/day if young, healthy, no heart disease[3]
- 12.5-25 ug/day if heart disease suspected*
- 25-50 ug/day if > 60 years of age[3]
- take on empty stomach 30-60 minutes before coffee or breakfast[3]
- increase to 75-150 ug/day after 3-4 months
- dose increases every 6 weeks
- dose increments 12.5-25 ug/day
- in the elderly[4]
- begin 25 ug/day
- increase by 25 ug every 6 weeks
- average dose to normalize TSH is 75 ug QD
- measure serum TSH after 3-4 months (decrease is slow)
- adjust to normalize serum TSH
- target serum TSH 1.0-2.5 uIU/mL[3]
- serum TSH < or > 0.4-4.0 uIU/mL associated with risks for ischemic heart disease, heart failure, fracture & all-cause mortality[31]
- low-normal serum TSH of no added benefit[13]
- dosage adjustments every 6 weeks
- target serum TSH 1.0-2.5 uIU/mL[3]
- if secondary hypothyroidism due to pituitary insufficiency
- monitor serum free T4; serum free TSH is low (& useless)
- adjust thyroxine replacement to keep serum free T4 in mid to upper 1/2 of normal range[3]
- adjust to normalize serum TSH
- increases of thyroxine of may be required with:
- pregnancy (25-50 ug/day, 30%)[9]
- with progression of thyroid destruction in Hashimoto's thyroiditis
- following thyroidectomy or radioiodine ablation of the thyroid
- decreases of thyroxine may be required with:
- spontaneous disappearance of TSH-receptor blocking autoantibodies
- increases in stimulatory TSH-receptor autoantibodies (reactivation of Grave's disease)
- emergence of autonomy & hyperfunction in patients with nodular goiter
- combination of T3/T4 offers no benefit over T4 alone[6][7] but some patients claim they feel better on T3/T4#[11]
- screening not recommended: insufficient data to recommend for or against screening for thyroid disease in non-pregnant adults[18]
Caution:
* coronary artery disease may be exacerbated by treatment of hypothyroidism. Start thyroxine 12.5-25 ug/day. Increase slowly.
* adrenal failure may be associated with both primary & secondary hypothyroidism & may be exacerbated by therapy.
Emergency therapy (hypotension, hypoventilation, lethary/coma) [rarely necessary] (GRS9)[24]
- administer hydrocortisone prior to administration of levothyroxine[3]
- 50-100 ug thyroxine IV every 6 hours for 24 hours, monitor EKG (see myxedema coma)
# propranolol & glucocorticoids may inhibit conversion of T3 to T4[11]
More general terms
More specific terms
- cretinism (congenital hypothyroidism)
- hypothyroidism during pregnancy
- idiopathic primary hypothyroidism; atrophic autoimmune thyroiditis
- myxedema coma; hypothyroid coma
- subclinical hypothyroidism
Additional terms
- Addison's disease (primary adrenal failure)
- desiccated thyroid (Armour, Niva, Apur)
- free thyroxine index (fT4I)
- Hashimoto's thyroiditis; chronic lymphocytic thyroiditis; struma lymphomatosa; lymphadenoid goiter; primary myxedema
- T3 total in serum/plasma
- thyroid-stimulating hormone (TSH) in serum; thyrotropin in serum
- thyroid-stimulating hormone (TSH) or thyrotropin
- thyroxine (T4)
- thyroxine [T4] (free) in serum
- thyroxine [T4] (total) in serum
- triiodothyronine [T3] (free) in serum
References
- ↑ Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 465
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 54, 749
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ 4.0 4.1 4.2 Solomon DH, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ 5.0 5.1 5.2 Journal Watch 22(7):51, 2002 Hollowell JG et al Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87:489, 2002 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11836274
- ↑ 6.0 6.1 Journal Watch 23(23):185-86, 2003 Walsh JP et al Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 88:45431, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14557419
Sawka AM et al Does a combination regimen of thyroxine (T4) and 3,5,3'- triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 88:4551, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14557420 - ↑ 7.0 7.1 Journal Watch 24(2):16, 2004 Clyde PW et al Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 290:2952, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14665656
Cooper DS Combined T4 and T3 therapy--back to the drawing board. JAMA 290:3002, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14665664 - ↑ 8.0 8.1 Journal Watch 24(5):41, 2004 US Preventive Services Task Force (USPSTF) Screening for thyroid disease: recommendation statement. Ann Intern Med 140:125, 2004 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/14734336 <Internet> http://www.ahrq.gov/clinic/3rduspstf/thyroid/thyrrs.htm
Helfand M; U.S. Preventive Services Task Force. Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 140:128 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/14734337 <Internet> http://www.endo-society.org/education/evidence-report.cfm
Surks MI et al Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291:228, 2004 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14722150 - ↑ 9.0 9.1 Journal Watch 24(16):130-31, 2004 Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004 Jul 15;351(3):241-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15254282
- ↑ 10.0 10.1 Prescriber's Letter 11(9): 2004 Management of Hypothyroidism in Pregnancy Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=200913&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 11.0 11.1 11.2 Prescriber's Letter 12(5): 2005 Combination Liothyronine (T3) and Levothyroxine (T4) Supplementation for Hypothyroidism Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=210512&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Roos A, Linn-Rasker SP, van Domburg RT, Tijssen JP, Berghout A. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med. 2005 Aug 8-22;165(15):1714-20. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16087818
- ↑ 13.0 13.1 Walsh JP, Ward LC, Burke V, Bhagat CI, Shiels L, Henley D, Gillett MJ, Gilbert R, Tanner M, Stuckey BG. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial. J Clin Endocrinol Metab. 2006 Jul;91(7):2624-30. Epub 2006 May 2. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16670161
- ↑ 14.0 14.1 Orstavik K et al, Pain and small fiber neuroapathy in patients with hypothyroidism. Neurology 2006, 67:786 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16966538
- ↑ 15.0 15.1 15.2 15.3 Garber JR et al Clinical Practice Guidelines for Hypothyroidism in Adults: Co-sponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association Thyroid, Sept 2012 http://online.liebertpub.com/doi/pdfplus/10.1089/thy.2012.0205 (corresponding NGC guideline withdrawn Nov 2017)
- ↑ Vaidya B, Pearce SH. Management of hypothyroidism in adults. BMJ. 2008 Jul 28;337:a801. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18662921
- ↑ 17.0 17.1 Iyasere CA et al Case 38-2014 - An 87-Year-Old Man with Sore Throat, Hoarseness, Fatigue, and Dyspnea. N Engl J Med 2014; 371:2321-2327. December 11, 2014 http://www.nejm.org/doi/full/10.1056/NEJMcpc1410935
- ↑ 18.0 18.1 LeFevre ML et al Screening for Thyroid Dysfunction: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. Published online 24 March 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25798805 <Internet> http://annals.org/article.aspx?articleid=2208599
- ↑ 19.0 19.1 Rabin AS, Hamnvik OP, Robinson ES, Miller AL, Loscalzo J. CLINICAL PROBLEM-SOLVING. Springing a Leak. N Engl J Med 2015; 373:1362-1367. October 1, 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26422727 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcps1401950
- ↑ Gaitonde DY, Rowley KD, Sweeney LB Hypothyroidism: an update. Am Fam Physician. 2012 Aug 1;86(3):244-51. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22962987 Free Article
- ↑ Garber JR, Cobin RH, Gharib H et al Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18(6):988-1028. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23246686 (corresponding NGC guideline withdrawn Nov 2017)
- ↑ Persani L Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012 Sep;97(9):3068-78 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22851492
- ↑ Devdhar M, Ousman YH, Burman KD. Hypothyroidism. Endocrinol Metab Clin North Am. 2007 Sep;36(3):595-615, v. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17673121
- ↑ 24.0 24.1 Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
- ↑ Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am. 2012 Mar;96(2):203-21. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22443971
- ↑ 26.0 26.1 Melville NA Hypothyroidism After TKIs for Cancer Linked to Longer Survival. Medscape - May 09, 2018 https://www.medscape.com/viewarticle/896383
Lechner MG, Vyas CM, Hamnvik OR et al Hypothyroidism During Tyrosine Kinase Inhibitor Therapy Is Associated with Longer Survival in Patients with Advanced Nonthyroidal Cancers. Thyroid. 2018 Apr;28(4):445-453. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29652597 - ↑ Centanni M, Benvenga S, Sachmechi I. Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report. J Endocrinol Invest. 2017 Dec;40(12):1289-1301. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/28695483 Free PMC Article
- ↑ Hennessey JV. The emergence of levothyroxine as a treatment for hypothyroidism. Endocrine. 2017 Jan;55(1):6-18. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/27981511
- ↑ 29.0 29.1 Shivaprasad KS, Siddardha K. Pituitary Hyperplasia from Primary Hypothyroidism. N Engl J Med 2019; 380:e9. Feb 21, 2019 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30786191 https://www.nejm.org/doi/full/10.1056/NEJMicm1805378
- ↑ Beck-Peccoz P, Rodari G, Giavoli C, Lania A. Central hypothyroidism - a neglected thyroid disorder. Nat Rev Endocrinol. 2017 Oct;13(10):588-598. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/28549061
- ↑ 31.0 31.1 Thayakaran R et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: Longitudinal study. BMJ 2019 Sep 3; 366:l4892 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31481394 Free PMC Article https://www.bmj.com/content/366/bmj.l4892
- ↑ 32.0 32.1 32.2 NEJM Knowledge+ Hematology
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