Hypothyroidism Hypothyroidism Dra Roopa by yaofenjin

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            Dra Roopa Mehta
   Departamento de Endocrinología y
Instituto Nacional de Ciencias Médicas y
            Salvador Zubirán

•   This is the most common pathological hormone
•   The deficiency of thyroid hormones results in a slowing
    down of metabolic processes

•   Prevalence 2-3% in the general population

•   Mean age at diagnosis is mid-50s

•   Male: Female 1:10

• Classification:
  Time of onset:              Congenital or acquired
  Severity:                   Clinical or subclinical
  Site of dysfunction:        Primary or secondary/tertiary

• Pathogenesis:
  The most characteristic finding is the accumulation of
  glycosaminoglycans (mostly hyaluronic acid) in
  interstitial tissue. This results in interstitial edema (e.g. in
  skin, heart muscle etc.). The accumulation is due to
  decreased destruction of glycosaminoglycans.
            Congenital hypothyroidism

•    Incidence :    1 in 4000
•    Male: Female 1:2
•    The most common cause worldwide is endemic
     iodine deficiency (<100mcg/day)
•    In areas with sufficient iodine intake: 85% sporadic /
     15% hereditary
1.   Thyroid dysgenesis (aplasia, hypoplasia and ectopic
     gland). (Associated with mutations in the genes for
     PAX8 and TTF-2 (transcription factors involved in
     morphogenesis and differentiation of thyroid gland)
            Congenital hypothyroidism

2.   Dyshormonogenesis. Defects in thyroid hormone
     synthesis, secretion or utilization (autosomal
     recessive). Include mutations in genes for thyroid TSH
     receptor, thyroid peroxidase gene, iodine transporter
     and thyroglobulin.
     Also mutations in genes for transcription factors
     needed for pituitary thyrotrope differentiation (pit-1,
     prop-1, HES-X)
3.   Failure of thyroid descent- “ectopic” poorly functioning
4.   Maternal radioactive iodine treatment/ antithyroid
     drugs (propylthiouracil)
5.   Transplacental transfer of TSH receptor (blocking)
     antibody from mother with Hashimotos thyroiditis
              Congenital hypothyroidism
Jaundice, lethargy, feeding
problems, respiratory problems,
constipation, hypothermia
• Puffy face, goiter
• Protruding tongue
• Hoarse cry
• Distended abdomen
• Umbilical hernia
• Muscle weakness (cannot sit
   up without help)
• Slow reflexes
            Congenital hypothyroidism

• Diagnosis:
  Neonatal screening. Heel prick test 24-48 hrs after birth.
  A low T4 (<6ug/dl) and elevated TSH (>30uU/ml)
  Marked retardation of bone maturation. Absence of
  proximal tibial and distal femoral epiphysis suggests
• Treatment: Replacement therapy

• Children: growth failure and mental retardation
• Adolescents: growth failure and precocious puberty may
  occur (pituitary hypertrophy)
              Primary hypothyroidism

•    Disease of thyroid characterised by low serum T4 and
     high serum TSH (above reference values)
•    In adults >65 years incidence is approx. 10%
•    Overall incidence in population is 1-2%

•    Two forms of primary hypothyroidism:

1.   Overt hypothyroidism (low free T4, high TSH)
2.   Subclinical hypothyroidism (normal free T4 and T3,
     high TSH)
           Causes of primary hypothyroidism

•    Most        frequent    causes      of     overt/subclinical
     hypothyroidism- 1-4 :
1.   Chronic autoimmune (Hashimoto´s) thyroiditis
2.   Thyroid surgery (2-4 weeks following after total
3.   Radiation treatment I131 (for treatment of Graves commonly)
4.   Drugs: iodine deficiency or excess, methimazole,
     propylthiouracil, lithium, amiodarone, interferon alpha
5.   Excessive iodine intake (radiocontrast dye, kelp)
6.   Infiltrative diseases- rare (e.g. hemochromatosis,TB,
     leukemia, amyloid etc.)
7.   Thyroiditis
               Chronic autoimmune thyroiditis
• Most common cause in iodine sufficient areas

• Male: Female    1:7
• Goitrous and atrophic forms- differ in extent of lymphocytic
  infiltration, fibrosis, and thyroid follicular cell hyperplasia
• Hypothyroid or euthyroid
• Associated    autoimmune       diseases:   polyglandular
  syndromes 1 and 2, vitiligo, pernicious anemia etc.
            Chronic autoimmune thyroiditis
• Pathogenesis:
• Cell and antibody mediated destruction of thyroid gland

• Diffuse lymphocytic infiltrate + circulating autoantibodies
  Lymphocytes become sensitized to thyroid antigens
  resulting in formation of autoantibodies: thyroperoxidase
  (TPO in 95%), thyroglobulin (Tg in 60%) and TSH
  receptor blocking antibody (TSH-R )
• Genetic        predisposition:      HLA-DR5,         HLA-B8
  histocompatibility antigens
•   Yellow arrows = lymphoid
    aggregates with germinal
•   Red arrows = diffuse
    lymphocytic infiltrate
•   Blue arrows = small atrophic
    follicles lined by hurtle cells
             Drugs causing hypothyroidism

• Methimazole/ Thiamazole: Block biosynthesis of thyroid
  hormones by inhibiting production of thyroid peroxidase
• Propylthiouracl: In addition blocks peripheral conversion
  of T4-T3
• Iodine: Deficiency and excess (inhibition of iodide
  organification and T4 and T3 synthesis esp. with
  underlying autoimmune disease)

•   Lithium: interferes with release of thyroid hormones, causing transient
    elevation of TSH in a third and persistent hypothyroidism in 10% (esp. with
    underlying autoimmune disease)
•   Amiodarone (iodine containing): inhibits thyroid hormone production and
    peripheral conversion (esp. with underlying autoimmune disease)
    22% with overt or mild hypothyroidism in one study. Long half life (40-100d)
        Drugs causing hypothyroidism

                                Thionamides, lithium,
Inhibition of thyroid hormone   aminoglutethimidine, iodine and
synthesis and/or release        iodine containing drugs
                                (amidarone, kelp, contrast)
                                 Cholestyramine, calcium
Decreased absorption of T4       carbonate, omeprazole, iron
                                 sulphate, raloxifene,

Immunedysregulation (ABs)        Interferon alpha, interleukin-2

   Destructive thyroiditis                 Sunitinib
          Transient primary hypothyroidism

• Subacute thyroiditis (granulomatous/Quervains)
  viral in origin (coxackie, mumps, adenovirus)
  fever/malaise and tender thyroid
  unilateral hard mass

• Lymphocytic thyroiditis (painless/silent/postpartum)
  Usually in postpartum women (2-12 weeks) (8% of
  postpartum women)
  painless thyroid enlargement
  80% with elevated TPO antibodies
          Transient primary hypothyroidism

• Both conditions have low RAIU
• Both present with transient hyperthyroidism (4-8 weeks)
  followed by a euthyroid phase. Patients may remain
  euthyroid or progress to a hypothyroid phase that lasts
  2-3 months followed by recovery (85% SAT, 75% LT)
• Patients often need temporary replacement therapy
• In LT, persistent thyroid abnormalities such as goiter
  and/or frank hypothyroidism occur in one third of
  patients. Recurrence probable in subsequent pregnancy
Transient primary hypothyroidism
           Subclinical hypothyroidism

• Asymptomatic state (subclinical symptoms) with normal
  serum and free T4 but elevated TSH
• Prevalence 4-8.5%; up to 15% in women >60 years
• Causes same as for overt hypothyroidism- commonly
  chronic   autoimmune      thyroiditis, post  radiation,
  inadequate replacement therapy

• Continuum between euthyroidism and hypothyroidism
• The distinction between a normal TSH and elevated TSH
  is arbitrary
• Is treatment recommended???
           Subclinical hypothyroidism

• Symptoms of hypothyroidism; weight gain
• Neuropsychiatric symptoms: depression, loss of memory
• Neuromuscular symptoms: >CPK, weakness, peripheral
• Coronary artery disease (atherosclerosis) and cardiac
  dysfunction (reduced myocardial contractility); >CRP
• Elevated total and LDL cholesterol
• Progression to overt hypothyroidism
           Subclinical hypothyroidism

• Arguments for treatment
  Reduction of risk for CV disease (improve myocardial
  function and lower LDL), prevention of goiter growth and
  improvement in subclinical symptoms

• Arguments against treatment
  Cost, lifelong commitment to medication in asymptomatic
  patients, risk of angina and arrhythmias in susceptible
            Subclinical hypothyroidism

• In patients with TSH levels >10mU/L-
  Treat with T4 to reduce CAD risk and prevent
  progression to overt hypothyroidism (especially in
  patients with high serum TPO antibody titers and

• TSH between 4.5-10mU/L: some studies have shown
  risk for CAD and presence of hypothyroid symptoms
             Subclinical hypothyroidism

• When evaluating such patients take into account:
  Clinical manifestations (symptoms and/or goiter)
  Presence of TPO antibodies
  Women of reproductive age with infertility or pregnant
  Progression of TSH levels with time (can normalise)

• TSH between 3-4.5mU/L: only significant risk appears to
  be progression to overt hypothyroidism over time
      Secondary and Tertiary hypothyroidism

• Account for <1% of patients with hypothyroidism
  (adulthood or childhood)
• Inappropriately low or normal TSH concentration (in
  presence of low T4 and T3)
• Secondary hypothyroidism caused by TSH deficiency
  (often      pituitary  tumors,  Sheehan's    syndrome,
• Tertiary hypothyroidism caused by TRH deficiency
  (hypothalamic damage from tumors, trauma, radiation,
  infiltrative diseases)
• Secondary and tertiary hypothyroidism cannot be
  distinguished by biochemical tests- MRI should be
  requested (mass lesion), other hormone deficiencies
               Clinical manifestations of
• Depends on degree of hormone deficiency (overt,

• Depends on speed of development          of   hormone
  deficiency (gradual, better tolerated)
                   Signs and symptoms

• SYMPTOMS                          Dry skin and hair loss
Fatigue/ lethargy                   Weight gain /Carpal tunnel synd.
Non-pitting edema of face           Menstrual irregularities
(periorbital edema) and hands       Growth retardation in children
Paraesthesias                       Deficiency of other hormones
Deep hoarse voice                   • SIGNS
Loss of memory/<Concentration       Yellowish tinge to skin
Somnolence/ Cold intolerance           (>carotenes)
Depression                          Bradycardia
Constipation (ileus)                Systemic arterial hypertension
Arthralgia/ Myalgia with proximal   Goiter or small thyroid
weakness                            Dry, cold skin
                                    Slow reflexes
              Clinical Manifestations

  Impaired muscle contraction, bradycardia and reduced
  cardiac output. Hypertension- >Peripheral vascular
  Cardiac enlargement due to interstitial edema but often
  due to pericardial effusion
  Low voltage complexes on ECG
  Hypoventilation -Respiratory muscle weakness
                     -Impaired ventilatory response to
                     hypoxia and hypercapnia
                     -Sleep apnea (retention of CO2)
              Clinical Manifestations

     Slowing of peristalsis leads to constipation
•    ANEMIA:
     Usually normochromic, normocytic anemia-
1.   Impaired Hb synthesis due to thyroxine deficiency
2.   Iron def. due to menorrhagia and impaired intestinal
3.   Folate deficiency from impaired intestinal folate
4.   Pernicious anemia with Vit-B12 def. megaloblastic
               Clinical Manifestations

  Oligo / amenorrhea (16%)         Menorrhagia (7%)
  Hyperprolactinemia occurs because of absence of
  inhibitory effect of thyroid hormone on prolactin secretion
  and causes galactorrhea and amenorrhea

  Carpal tunnel syndrome
  >CPK- muscle cramps, proximal weakness
  Slow relaxing reflexes
              Clinical Manifestations

  Decreased glomerular filtration rate
  -Impaired ability to excrete a water load (hyponatremia)

  Glycosaminoglycan, mainly hyaluronic acid, accumulate
  in skin and tissues causing retention of sodium and
  water- puffy skin
  Reduced blood flow and calorigenesis- hypothermia and
  decreased sweating
  Loss of lateral eyebrows
              Clinical Manifestations

  Hyponatremia (<free water clearance because of
  inappropriate ADH production)
  Hyperlipidemia: reduced number of lipoprotein lipase
  receptors, reduced degradation of lipoproteins and
  reduced lipoprotein lipase activity
      (4.2% of patients with hyperlipidemia
      • Hypercholesterolemia 56%
      • Hypertriglyceridemia 1.5%
      • Mixed hyperlipidemia 34%)
                   Diagnostic tests

• Clinical evaluation
• Measure T4 (total or free), T3 (total or free) and TSH
• Thyroid antibodies:      anti TPO
                           anti Tg
• Cerebral MRI / CT when searching for mass lesion
  (Enlargement of pituitary also occurs in primary
  hypothyroidism due to hyperplasia of thyrotropes)
• TRH test for diagnosis of central hypothyroidism
                     Suspicion of hypothyroidism

                          Thyroid function tests


        Goiter                                 Normal size or small thyroid

     Increased TSH
                                                   TSH normal or reduced

 Primary hypothyroidism                            Central hypothyroidism

T3    + T4       + TSH                        T3 + T4 + TSH nl /

         Primary hypothyroidism                     Central hypothyroidism

 Anti thyroid AB+             Anti thyroid AB-

                                  Drugs:         Surgery or tx 131I
Autoimmune     Postpartum        Lithium
 thyroiditis    thyroiditis     Amiodarone
                                                          Pituitary MRI or CT
                                                                TRH test

• Normal metabolic state should be restored gradually as
  rapid increase in metabolic rate may precipitate cardiac
• Thyroxine (100mcg) or mixture of T3(20mcg) and
• Exclude adrenal insufficiency before initiating tx.
• Given 1x daily in morning (T4 t1/2=7days)- fasting
• In elderly, with ischemic heart disease, initial dose 25ug;
  increased gradually at 4 week intervals
• Monitor improvement in clinical symptoms and
  normalization of TSH
• Secondary hypothyroidism- free T4 used for monitoring
  response to tx.
           Factors that increase the requirement
                           for T4
• Pregnancy, Estrogen therapy, Weight gain

• Drugs which increase catabolism of T4:
Rifampin, Carbamazepine, Phenytoin, Phenobarbitol

• Malabsorption or increased excretion of T4:
Gastrointestinal disorders, Impaired acid secretion

• Drugs which interfere with T4 absorption:
Ferrous sulfate, Cholestyramine or colestipol, Sucralfate
Aluminum hydroxide gels, Calcium Carbonate, Sertraline
Raloxifene, Omeprazole

• Nephrotic syndrome
• Progressive thyroid dysfunction
              Potential causes of TSH elevation in
             thyroxine-treated patients with primary
• Suboptimal dosing: Inadequate prescribed dosage, noncompliance,
  dispensing error (incorrect dose or formulation change)

• Progressive decrease in endogenous thyroxine production:
  Autoimmune thyroiditis, Previous thyroid irradiation

• Reduced thyroxine absorption
  Drug interactions: Iron, Calcium carbonate, Cholestyramine,
  Aluminum hydroxide gel, Sucralfate, dietary soy and fiber
  Comorbid conditions: Disorders causing malabsorption - eg, celiac
  disease, previous small bowel surgery

• Increased thyroxine clearance
  Drug interactions: Phenytoin, Carbamazepine, Phenobarbitol etc.
  Coexisting conditions: Pregnancy, Nephrotic syndrome
• Other: Postmenopausal hormone replacement therapy
                 Myxedema Coma

• End-stage of     untreated    hypothyroidism-   medical

• Clinical manifestations:
  Decreased mental status, hypothermia, bradycardia,
  hypotension, hypoventilation (>pCO2), hypoglycemia,
  typical myxedematous facies and skin, hyponatremia
  (impaired water excretion and disordered regulation of
  vasopressin secretion), slow relaxing reflexes, coma and

  Precipitated by intercurrent illness such as infection,
  stroke or CNS depressants
  If untreated 100% mortality
                 Myxedema Coma

• Identify and treat intercurrent illness
• Antibiotic therapy after blood cultures
• Passive external rewarming for hypothermia. 0.5degrees
  celsius / hr
• Warm humidified O2, mechanical ventilation if necessary
  and cardiac monitor for arrhythmias
• Correct hyponatremia (fluid restriction), hypotension and
• Take blood for TFTs and cortisol before starting tx. If
  hypocortisolemic start hydrocortisone
• T4 300-500ug iv followed by 50-100ug / daily
  If no response within 24-48hrs, T3 10ug iv 8 hourly
                    CASO CLINICO
• Mujer de 27 años con antecedentes familiares de
  enfermedad tiroidea (una tía materna con enfermedad de
  Graves y una hermana con hipotiroidismo)
• Ciclos menstruales regulares hasta hace dos años,
  actualmente 40-60 x 2-3
• Un año con piel seca, fatiga y estreñimiento
• EF: peso 68 kg (previo 63), TA 130/70 FC 58 x min
• Edema bipalpebral, piel seca, tiroides palpable pequeña,
  ROTS lentos
          CASO CLINICO

CT3     0.65       (0.75 -1.25)
T3      1 nmol/l   (1.16 -3.86)
T4      65 nmol/l (77.2-154.4)
TSH     10 mU/l    (0.5-3.5)
Tg      5 ng/ml      (0-30)
AcTPO   1:25,000   (negativos)
AcTg    negativos (negativos)
                 CASO CLINICO

• A 29 year old woman with a history of a diffuse goiter
  with normal TFTs. She gave birth to a healthy baby 4
  months ago. A month ago she developed symptoms of
  tremor, irritability and mild heat intolerance.
  T4           14.3ug/dl (4.5-12)
  TSH          0.03mIU/ml (0.32-5)
  Today she has fatigue, dry skin, somnolence and
  difficulty concentrating at work
  On examination, 92kg, 130/70, no lid lag or
  exophthalmus. Thyroid diffusely enlarged. No bruit.
  Family history of Graves disease
                  CASO CLINICO

• Does this woman have Graves disease?

  New TFTs:         free T4      0.6ng/dl (0.7-2.2)
                    T3           78ng/dl (80-200)
                    TSH          27.3mIU/ml (0.32-5)

• What is the diagnosis? How is it treated?
                  CASO CLINICO

• A 51 year old man presents with a 5 week history of right
  sided neck pain radiating to right ear. He has had a mild
  URTI 7 weeks ago. He is physically fit with a normal
  pulse of 50; but in last 2 weeks this has risen to 70. He
  feels nervous and irritable.
  On examination, slightly enlarged tender thyroid gland,
  with no lymphadenopathy.
  TFTs:      free T4        1.9ng/ml (0.7-2.2)
             TSH            0.03mIU/ml (0.32-5.00)
  U/S        diffusely enlarged thyroid gland
  RAU scan 2hr uptake 1.9%        24hr 2.3% (Norm=20%)
                   CASO CLINICO

•    What disorder does this man have?

•    Appropriate treatments include:
1.   Surgery
2.   Prophylthiouracil or methimazole
3.   Propranalol
4.   Ibuprofen
5.   Predisolone
6.   Radioactive iodine
                  CASO CLINICO

• 72 year old woman brought to ER in respiratory arrrest
  (respiratory frq-6). Not responsive. Family says she has
  been disorientated last 2 weeks. PMH: depression,
  hypothyroidism, and peptic ulcer disease. (captopril,
  levothyroxine, ranitidine)
• On examination minimally responsive. Thin woman. Cool
  dry skin. Bilateral crepitations on pulmonary examination
  Temperature 95 farenheit
• Intubated and mechanically ventilated
  Na          119mmmol/l (135-145)
  K           3.7mmol/l      (3.5-5.2)
                 CASO CLINICO

  Arterial pH            7.31 (7.35-7.45)
  Plasma osmolality      258mOsm/kg (270-290)
  Toxicology negative

What tests would you ask for?
Why might hyponatremia be present?
How should this patient be treated?

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