II. Definitions

  1. Hypothyroidism
    1. Inadequate Thyroid Hormone production from the Thyroid Gland OR
    2. Insufficient stimulation from the Hypothalamus or the Pituitary Gland

III. Epidemiology: Prevalence (US)

  1. Congenital: 1 in 4000 newborns
  2. Adults:
    1. Age over 65 years: 2-4% (especially older women)
    2. Overall in U.S.: 0.3-1.0%
    3. Undiagnosed cases: 13 Million estimated in U.S.
  3. Gender
    1. More common in women by 7 fold
    2. Men: 6 per 10,000
    3. Women: 40 per 10,000

IV. Physiology

V. Risk Factors

  1. Autoimmune Disorders
    1. Diabetes Mellitus
    2. Celiac Sprue
    3. Adrenal Insufficiency (Addison Disease)
    4. Autoimmune Gastric Atrophy
  2. Congenital Disorders
    1. Down Syndrome
    2. Turner Syndrome
  3. Iatrogenic
    1. Subtotal Thyroidectomy
    2. Neck Radiation Therapy
    3. Radioactive Iodine
    4. See Medications Affecting Thyroid Function

VI. Causes

  1. Hashimoto's Thyroiditis (Most common cause)
  2. Congenital Causes
    1. Congenital Hypothyroidism (Cretinism)
    2. Down Syndrome
    3. Turner Syndrome
  3. Thyroid ablation
    1. Graves' Disease Management
      1. Radioactive Iodine (I-131)
      2. Thyroidectomy
    2. Neck radiation in cancer treatment
      1. Hodgkin's Lymphoma
      2. Laryngeal Cancer
  4. Medications
    1. See Medications Affecting Thyroid Function
    2. Severe Iodine deficiency (rare in U.S. due to iodinated salt)
  5. Secondary Hypothyroidism (Central causes, only 5% of cases)
    1. Congenital Hypopituitarism
    2. Pituitary necrosis (Sheehan's Syndrome)
    3. Pituitary or Hypothalamic lesion
    4. HIV Infection on highly active Antiretrovirals
      1. Also associated with low CD4 Counts
      2. Beltran (2003) Clin Infect Dis 37:579-83 [PubMed]
  6. Transient Hypothyroidism
    1. Postpartum Thyroiditis
    2. Subacute Thyroiditis
    3. Silent Thyroiditis
    4. TSH receptor blocking Antibody associated Thyroiditis

VII. Symptoms

  1. Generalized
    1. Fatigue or generalized weakness (99%)
    2. Lethargy (91%)
    3. Cold intolerance (89%)
    4. Weight gain despite diminished food intake
    5. Edema
    6. Arthralgias
    7. Myalgias
  2. Neuropsychiatric
    1. Diminished libido
    2. Headache
    3. Hoarseness
    4. Slow thinking
    5. Forgetfulness (66%)
    6. Slow speech (91%)
    7. Depressed Mood
    8. Difficult Concentration
  3. Gastrointestinal
    1. Constipation (61%)
  4. Dermatologic
    1. Dry or coarse skin (97%)
    2. Decreased Sweating (89%)
    3. Hair Loss (especially outer third of eyebrows)
    4. Broken nails
  5. Gynecologic
    1. Amenorrhea or Menorrhagia
    2. Infertility

VIII. Symptoms: Presentations

  1. Most specific symptoms for Hypothyroidism
    1. Constipation
    2. Cold Intolerance
    3. Dry Skin
    4. Proximal Muscle Weakness
    5. Hair thinning or Hair Loss
  2. Infants and children
    1. Lethargy
    2. Failure to Thrive
  3. Women
    1. Irregular Menses
    2. Infertility
  4. Older patients
    1. Cognitive decline

IX. Signs

  1. General
    1. Round puffy face or other Facial Edema (79%)
    2. Periorbital edema or Eyelid Edema (90%)
    3. Large, thick Tongue or Macroglossia (82%)
    4. Non-pitting ankle edema
    5. Hypothermia
  2. Neuropsychiatric
    1. Slow speech
    2. Hoarse voice
    3. Hypokinesia
    4. Generalized Muscle Weakness
    5. Delayed relaxation of Deep Tendon Reflexes
      1. Patellar Reflex
      2. Ankle Jerk reflex
  3. Dermatologic
    1. Cold, dry, thick Scaling skin
      1. Affects palms, soles, elbows and knees
      2. Skin may show yellow-orange discoloration
    2. Dry coarse brittle hair (76%)
    3. Dry, longitudinally ridged nails
    4. Lateral eyebrow thinning
  4. Gastrointestinal
    1. Ascites
  5. Cardiopulmonary
    1. Faint cardiac impulse
    2. Indistinct heart tones
    3. Cardiac enlargement
    4. Bradycardia
    5. Pericardial Effusion (severe Hypothyroidism)
    6. Pleural Effusion (severe Hypothyroidism)
    7. Variable effect on Blood Pressure
      1. Hypotension may be present
      2. Diastolic Hypertension
        1. Dernellis (2002) Am Heart J 143:718-24 [PubMed]

XI. Labs: Thyroid Function Tests

  1. See Thyroid Function Testing
  2. TSH is the primary screening and monitoring test
    1. Most sensitive marker for Thyroid function
  3. Indications for Screening
    1. Pregnancy
    2. All elderly with depression
    3. All elderly entering long term care
    4. Risk Factors (see above)
      1. Autoimmune disorders (e.g. Diabetes Mellitus, Celiac Disease)
      2. Congenital disorders (Turner Syndrome, Down Syndrome)
      3. Iatrogenic (e.g. Subtotal Thyroidectomy, Neck Radiation Therapy, Radioactive Iodine)
      4. Medications Affecting Thyroid Function
  4. Protocol
    1. Monitoring after diagnosis: TSH alone is sufficient
    2. Screening: TSH with reflex to Free T4
  5. Interpretation
    1. Serum TSH increased
      1. Free T4 low
        1. Primary Hypothyroidism
      2. Free T4 normal
        1. Subclinical Hypothyroidism
        2. Overt Hypothyroidism unlikely if Serum TSH 6-10
        3. Consider checking Free T3
          1. Free T3 is low in congenital absence of T4 to T3 converting enzyme
          2. Free T3 may also be low due to Amiodarone blocking T4 to T3 conversion
    2. Serum TSH decreased
      1. Free T4 low: Central Hypothyroidism (secondary Hypothyroidism, rare <5% of cases)
        1. Urgent endocrinology Consultation
        2. Obtain head imaging (MRI Brain) with attention toward sella turcica
        3. Obtain other pituitary-related Hormone levels
          1. Serum FSH
          2. Serum LH
          3. Serum Prolactin
          4. Serum Cortisol
          5. Serum Testosterone (males)
      2. Free T4 high
        1. Hyperthyroidism

XII. Labs: Other

  1. Lipid profile
    1. LDL Cholesterol elevated
    2. Serum Triglyceride elevated
  2. Serum labs
    1. Creatine Phosphokinase (CPK) elevated
    2. Lactate Dehydrogenase (LDH) elevated
    3. Serum Prolactin increased (see Hyperprolactinemia)
    4. Serum Sodium decreased (see Hyponatremia)
  3. Blood count and acute phase reactants
    1. Complete Blood Count (CBC)
      1. Refractory Macrocytic Anemia or Normocytic Anemia
    2. C-Reactive Protein (C-RP) increased
  4. Urinalysis
    1. Proteinuria

XIII. Diagnostics: Electrocardiogram (EKG)

  1. Bradycardia
  2. Low amplitude QRS Complexes
  3. Flattened or inverted T Waves

XIV. Imaging

  1. Retarded bone growth

XV. Complications

  1. Hyperlipidemia
  2. Hypertension
  3. Infertility
  4. Neuromuscular dysfunction
  5. Myxedema Coma (rare, 0.22 per million persons)
  6. Atrial Fibrillation

XVI. Management: General

  1. See Thyroid Replacement (Levothyroxine)
  2. See Subclinical Hypothyroidism for treatment indications
  3. In general, avoid Liothyronine and desiccated Thyroid (no evidence of benefit, and cardiovascular risk)
  4. Elderly
    1. See Subclinical Hypothyroidism
    2. TSH elevations are often transient (often during non-Thyroid related acute conditions)
      1. Exercise caution when starting Thyroid Replacement in the elderly
      2. Consider rechecking TSH after acute illness before initiating Thyroid Replacement
      3. Wong (1981) Arch Intern Med 141(7):873-5 +PMID: 7235805 [PubMed]
    3. Consider withdrawing Thyroid Replacement
      1. Indication: Elderly in Community and nursing-home
      2. May have been diagnosed prior to sensitive TSH
      3. Trial at decreased dose or off for 6 weeks
      4. Recheck TSH after trial
  5. Pregnancy
    1. See Hypothyroidism in Pregnancy
    2. Maintaining a euthyroid state throughout pregnancy is critical

XVII. Management: Endocrinology referral indications

  1. Age <18 years old
  2. Cardiac disorders
  3. Concurrent other endocrine disorders
  4. Hypothyroidism in Pregnancy
  5. Thyroid Gland structural abnormality (e.g. Goiter or thryoid Nodule)
  6. Poor response to Thyroid Replacement

XVIII. Management: Persistent Symptoms despite normal range TSH

  1. See Fatigue
  2. Consider Drug Interaction with Levothyroxine
    1. See Levothyroxine
  3. Consider other causes
    1. Adrenal Insufficiency (rare)
    2. Chronic Kidney Disease
    3. Liver disease
    4. Sleep Apnea
    5. Mood Disorder
      1. Major Depression
      2. Anxiety Disorder
    6. Vitamin Deficiency or Anemia
      1. Vitamin B12 Deficiency
      2. Iron Deficiency Anemia
      3. Vitamin D Deficiency
    7. Infection
      1. Mononucleosis
      2. Lyme Disease
      3. HIV Infection
  4. Alternative replacement strategies are not typically recommended
    1. Dessicated Thyroid Hormone or Armour Thyroid
      1. Not recommended by American Association of Endocrinology
      2. T3 concentrations are high in Armour Thyroid and increase the risk of cardiovascular toxicity
    2. Combination T3 (Liothyronine, Cytomel) and T4 (Levothyroxine) Therapy
      1. See Liothyronine (Cytomel)
      2. T3 dosing is 1/14 of T4 dosing
      3. T3 should not be used alone without concurrent T4
      4. Adding T3 to T4 was initially found to improve neuropsychiatric symptoms
      5. Most studies suggest no benefit and are often associated with iatrogenic Hyperthyroidism
        1. Clyde (2003) JAMA 290:2952-8 [PubMed]
        2. Escobar-Morreale (2005) J Clin Endocrinol Metab 90(8):4946-54 [PubMed]

XIX. Management: Abnormal TSH despite previously stable dose

  1. Non-compliance with Thyroid Replacement (missed doses)
    1. Consider especially if doses >200 mcg/day
  2. Change in formulation (e.g. manufacturer change, or generic to brand name)
    1. Avoid changes in formulation and recheck TSH 4-6 weeks after such changes occur
  3. Hormonal changes
    1. Pregnancy (maintaining euthyroid state in pregnancy is critical)
    2. Oral Contraceptives or Estrogen Replacement started or stopped
  4. Decreased Levothyroxine absorption or Drug Interaction
    1. See Levothyroxine for Drug Interactions and Food Interactions
    2. Levothyroxine taken with meals

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Related Studies

Ontology: Hypothyroidism (C0020676)

Definition (NCI_CTCAE) A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland.
Definition (NCI) Abnormally low levels of thyroid hormone.(NICHD)
Definition (NCI_NCI-GLOSS) Too little thyroid hormone. Symptoms include weight gain, constipation, dry skin, and sensitivity to the cold.
Definition (CSP) deficiency of thyroid gland activity; characterized by decreased basal metabolic rate, fatigue and lethargy, sensitivity to cold, and menstrual disturbances; untreated it progresses to myxedema; in infants severe hypothyroidism leads to cretinism.
Definition (MSH) A syndrome that results from abnormally low secretion of THYROID HORMONES from the THYROID GLAND, leading to a decrease in BASAL METABOLIC RATE. In its most severe form, there is accumulation of MUCOPOLYSACCHARIDES in the SKIN and EDEMA, known as MYXEDEMA.
Concepts Disease or Syndrome (T047)
MSH D007037
ICD9 244.9
ICD10 E03.9
SnomedCT 190290003, 267465007, 237572004, 267377003, 190274003, 154660000, 40930008
LNC MTHU020783, LA14303-4
English Hypothyroidism, Hypothyroidisms, Unspecified hypothyroidism, HYPOTHYROIDISM, THYROID ACTIVITY DECREASED, Hypothyroidism, unspecified, hypothyroidism, hypothyroidism (diagnosis), Thyroid activity decreased, Hypothyroidism NOS, Hypothyroidism [Disease/Finding], hypothyroidisms, hypothyroid, Unspecified acquired hypothyroidism, Underactive Thyroid, Thyroid insufficiency, Thyroid deficiency, Hypothyroidism NOS (disorder), underactive thyroid, Hypothyroid, Hypothyroidism (disorder), deficiency; thyroid, insufficiency; thyroid, subthyroidism, thyroid; deficiency, thyroid; insufficiency, Hypothyroidism, NOS, Hypothyroidism [Ambiguous]
French HYPOTHYROIDIE, Hypothyroïdisme non précisé, Activité thyroïdienne diminuée, DIMINUTION ACTIVITE THYROIDIENNE, Hypothyréose, Hypothyroïdie, Hypothyroïdisme
Spanish HIPOTIROIDISMO, Hipotiroidismo no especificado, Actividad del tiroides disminuida, TIROIDES, ACTIVIDAD DISMINUIDA, hipotiroidismo, SAI (trastorno), hipotiroidismo, SAI, hipotiroidismo (trastorno), hipotiroidismo, Hipotiroidismo
German HYPOTHYREOSE, Schilddruesenaktivitaet erniedrigt, unspezifische Hypothyreose, Hypothyreose, nicht naeher bezeichnet, SCHILDDRUESENAKTIVITAET VERMINDER, Hypothyreose, Hypothyreoidismus
Dutch verlaagde schildklieractiviteit, niet-gespecificeerde hypothyroïdie, deficiëntie; schildklier, insufficiëntie; schildklier, schildklier; deficiëntie, schildklier; insufficiëntie, Hypothyroïdie, niet gespecificeerd, hypothyroïdie, Hypothyreose, Hypothyreoïdie, Thyreoïdie, hypo-
Italian Attività tiroidea diminuita, Ipotiroidismo non specificato, Ipotiroidismo
Portuguese Hipotiroidismo NE, Actividade tiroideia diminuída, DIMINUICAO DA ACTIVIDADE TIROIDEI, HIPOTIROIDISMO, Hipotiroidismo, Hipotireoidismo
Japanese 詳細不明の甲状腺機能低下症, 甲状腺機能低下症, 甲状腺機能低下, コウジョウセンキノウテイカ, コウジョウセンキノウテイカショウ, ショウサイフメイノコウジョウセンキノウテイカショウ
Swedish Hypotyreos
Finnish Kilpirauhasen vajaatoiminta
Czech Blíže neurčená hypotyreóza, Hypotyreóza, Snížená činnost štítné žlázy, hypotyreoidismus, hypotyreóza, hypothyreóza
Korean 상세불명의 갑상샘 기능저하증
Polish Niedoczynność tarczycy
Hungarian Hypothyreosis, Pajzsmirigy aktivitás csökkenése, Nem meghatározott hypothyreosis
Norwegian Hypotyreoidisme, Lavt stoffskifte, Hypotyreose

Ontology: Myxedema (C0027145)

Definition (NCI) A condition characterized by severe hypothyroidism that is caused by autoimmune thyroid gland disorders, surgical reduction of thyroid tissue, radiation exposure, and viral infections. Signs and symptoms include generalized fatigue, lethargy, increased body weight, pale, edematous and thickened skin, low blood pressure, constipation and cold intolerance.
Definition (CSP) condition characterized by a dry, waxy type of swelling with abnormal deposits of mucin in the skin and other tissues; it is produced by a functional insufficiency of the thyroid gland, resulting in deficiency of thyroid hormone.
Definition (MSH) A condition characterized by a dry, waxy type of swelling (EDEMA) with abnormal deposits of MUCOPOLYSACCHARIDES in the SKIN and other tissues. It is caused by a deficiency of THYROID HORMONES. The skin becomes puffy around the eyes and on the cheeks. The face is dull and expressionless with thickened nose and lips.
Concepts Disease or Syndrome (T047)
MSH D009230
ICD10 E03.9
SnomedCT 190274003, 154660000, 267465007, 43153006
English Myxedema, Myxedemas, MYXOEDEMA, MYXEDEMA, myxedema, myxedema (diagnosis), Myxedema NOS, Myxedema [Disease/Finding], Mucin in skin, Myxoedema, Myxedema (disorder), Hypothyroidism/myxoedema, Myxedema, NOS, Myxoedema, NOS, myxoedema
French MYXOEDEME, Myxoedème
Portuguese MIXEDEMA, Mixedema
Spanish MIXEDEMA, Mixoedema, mixedema (trastorno), mixedema, Mixedema
German MYXOEDEM, Myxoedem, Myxödem
Swedish Myxödem
Czech myxedém, Myxedém
Finnish Myksedeema
Dutch myxoedeem, Hypothyreoàdie/myxoedeem, Myxoedeem
Japanese ネンエキスイシュ, 粘液水腫
Polish Obrzęk śluzowaty
Hungarian Myxoedema
Norwegian Myksødem
Italian Mixedema