1. Hypothyroidism Dra Roopa Mehta
Departamento de Endocrinología y Metabolismo
Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán

2. Introduction This is the most common pathological hormone deficiency
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

3. Introduction 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.

4. 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
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)

5. Congenital hypothyroidism
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 thyroid
4. Maternal radioactive iodine treatment/ antithyroid drugs (propylthiouracil)
5. Transplacental transfer of TSH receptor (blocking) antibody from mother with Hashimotos thyroiditis

6. Congenital hypothyroidism
Symptoms:
Jaundice, lethargy, feeding
problems, respiratory problems,
constipation, hypothermia
Signs:
Puffy face, goiter
Protruding tongue (macroglossia)
Hoarse cry
Distended abdomen
Umbilical hernia
Muscle weakness (cannot sit up without help)
Slow reflexes

7. Congenital hypothyroidism
Diagnosis:
Neonatal screening. Heel prick test 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 hypothyroidism
Treatment: Replacement therapy
Children: growth failure and mental retardation
Adolescents: growth failure and precocious puberty may occur (pituitary hypertrophy)

8. 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:
Overt hypothyroidism (low free T4, high TSH)
Subclinical hypothyroidism (normal free T4 and T3, high TSH)

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

10. Chronic autoimmune thyroiditis (Hashimoto´s)
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.

11. Chronic autoimmune thyroiditis (Hashimoto´s)
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

12. Yellow arrows = lymphoid
aggregates with germinal
centers
Red arrows = diffuse
lymphocytic infiltrate
Blue arrows = small atrophic
follicles lined by hurtle cells

13. 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)

14. Drugs causing hypothyroidism
Inhibition of thyroid hormone synthesis and/or release
Thionamides, lithium, aminoglutethimidine, iodine and iodine containing drugs (amidarone, kelp, contrast)
Decreased absorption of T4
Cholestyramine, calcium carbonate, omeprazole, iron sulphate, raloxifene,
Immunedysregulation (ABs)
Interferon alpha, interleukin-2
Destructive thyroiditis
Sunitinib

15. 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

16. 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

17. Transient primary hypothyroidism

18. 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???

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

20. 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 patients

21. 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 >65years)
TSH between mU/L: some studies have shown risk for CAD and presence of hypothyroid symptoms

22. Subclinical hypothyroidism
When evaluating such patients take into account:
Clinical manifestations (symptoms and/or goiter)
Presence of TPO antibodies
Age
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

23. 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, surgery/radiotherapy)
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

24. Clinical manifestations of hypothyroidism
Depends on degree of hormone deficiency (overt, subclinical)
Depends on speed of development of hormone deficiency (gradual, better tolerated)

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

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

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

28. Clinical Manifestations
REPRODUCTIVE SYSTEM:
Oligo / amenorrhea (16%) Menorrhagia (7%)
Hyperprolactinemia occurs because of absence of inhibitory effect of thyroid hormone on prolactin secretion and causes galactorrhea and amenorrhea
NEUROMUSCULAR SYSTEM:
Carpal tunnel syndrome
>CPK- muscle cramps, proximal weakness
Slow relaxing reflexes

29. Clinical Manifestations
RENAL SYSTEM:
Decreased glomerular filtration rate
-Impaired ability to excrete a water load (hyponatremia)
SKIN AND HAIR:
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
Carotenemia.
Loss of lateral eyebrows

30. Clinical Manifestations
METABOLIC ABNORMALITIES:
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%)
Hyperhomocystinemia

31. 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

32. Hypothyroidism T3 + T4 + TSH T3 + T4 + TSH nl /
Suspicion of hypothyroidism
Thyroid function tests
Hypothyroidism
Normal size or small thyroid
Goiter
Increased TSH
TSH normal or reduced
Primary hypothyroidism
Central hypothyroidism
T T TSH
T3 + T4 + TSH nl /

33. Hypothyroidism Hypothyroidism Primary hypothyroidism
Central hypothyroidism
Anti thyroid AB+
Anti thyroid AB-
Drugs:
Lithium
Amiodarone
Etc.
Surgery or tx 131I
Autoimmune thyroiditis
Postpartum
thyroiditis
Pituitary MRI or CT
TRH test

34. Treatment
Normal metabolic state should be restored gradually as rapid increase in metabolic rate may precipitate cardiac arrhythmias
Thyroxine (100mcg) or mixture of T3(20mcg) and T4(100mcg)
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.

35. 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

36. Potential causes of TSH elevation in thyroxine-treated patients with primary hypothyroidism
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

37. Myxedema Coma End-stage of untreated hypothyroidism- medical emergency
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 death
Precipitated by intercurrent illness such as infection, stroke or CNS depressants
If untreated 100% mortality

38. 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 hypoglycemia
Take blood for TFTs and cortisol before starting tx. If hypocortisolemic start hydrocortisone
T ug iv followed by ug / daily
If no response within 24-48hrs, T3 10ug iv 8 hourly

39. 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 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

40. CASO CLINICO PFT’s CT3 0.65 (0.75 -1.25) T3 1 nmol/l (1.16 -3.86)
TSH mU/l ( )
Tg ng/ml (0-30)
AcTPO 1:25, (negativos)
AcTg negativos (negativos)

41. 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.
T ug/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

42. CASO CLINICO Does this woman have Graves disease?
New TFTs: free T4 0.6ng/dl ( )
T3 78ng/dl (80-200)
TSH 27.3mIU/ml (0.32-5)
What is the diagnosis? How is it treated?

43. 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 ( )
TSH 0.03mIU/ml ( )
U/S diffusely enlarged thyroid gland
RAU scan 2hr uptake 1.9% 24hr 2.3% (Norm=20%)

44. CASO CLINICO What disorder does this man have?
Appropriate treatments include:
Surgery
Prophylthiouracil or methimazole
Propranalol
Ibuprofen
Predisolone
Radioactive iodine

45. 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 ( )
K 3.7mmol/l ( )

46. CASO CLINICO Arterial pH 7.31 (7.35-7.45)
Plasma osmolality 258mOsm/kg ( )
Toxicology negative
What tests would you ask for?
Why might hyponatremia be present?
How should this patient be treated?