Diseases of thyroid gland

THYROID GLAND DISORDERS

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GENERAL ASPECTS OF THYROID GLAND

– Anatomy: weight range from 12 to 30g

– Located in the neck, anterior to the traquea

– Produces: T4 & T3 (active hormone)

– Regulation: “negative Feed-back” axis


THYROID GLAND DISORDERS– THYROID GLAND REGULATION

“negative Feed-back” axis

– Hypothalamus

(TRH positive effect)

– Pituitary gland

(TSH, positive effect)

– Thyroid gland

T3 & T4

(negative effect)



Thyroid hormones:

– T4: (Thyroxine) is made exclusively in thyroid gland

• Ratio of T4 to T3 ; 5::1

• Potency of T4 to T3; 1::10

• T4 is the most important source of T3 by peripheral tissue deiodination “ T4 to T3 “



Thyroid hormones:

– T3: (Triiodothyronine) main source is peripheral deiodination:

• Ratio of T3 to T4 ; 1::5

• Potency of T3 to T4; 10::1

• T3 is the most important because more than 90% of the thyroid hormones physiological effects are due to the binding of T3 to Thyroid receptors in peripheral tissues.



PHYSIOLOGY EFFECTS OF THYROID HORMONES

THEY ARE NOT ESSENTIAL FOR LIFE, BUT ARE EXTREMELY

HELPFUL



THYROID HORMONE EFFECTS:

– Affects every single cell in the body

• Modulates:

– Oxygen consumption

– Growth rate

– Maturation and cell differentiation

– Turnover of Vitamins, Hormones, Proteins, Fat, CHO



MECHANISMS OF THYROID HORMONE ACTION

– Act by binding to Nuclear receptors, termed Thyroid Hormone Receptors (TRs), Increasing synthesis of proteins

– At mitochondrial level increases number and activity to increasing ATP production

– At Cell membrane increases ions and substrates transmembrane flux



THYROID HORMONE EFFECTS

– CALORIGENESIS– GROWTH & MATURATION RATE– C.N.S. DEVELOPMENT & FUNCTION– CHO, FAT & PROTEIN METABOLISM– MUSCLE METABOLISM– ELECTROLYTE BALANCE– VITAMIN METABOLISM– CARDIOVASCULAR SYSTEM– HEMATOPOIETIC SYSTEM– GASTROINTESTINAL SYSTEM– ENDOCRINE SYSTEM– PREGNANCY




– CALORIGENESIS• Controls the Basal Metabolic Rate (BMR)

– CHO METABOLISM

• Increases:– Glucose absorption of the GI tract– Glucose consumption by peripheral tissues– Glucose uptake by the cells– Glycolysis– Gluconeogenesis– Insulin secretion




– GROWTH & MATURATION RATE

– C.N.S. DEVELOPMENT & FUNTION

• “ESSENTIAL” in the newborn to prevent development of “CRETINISMS” & to a normal “IQ”

• Modulation of brain cerebration

• Mood modulation




- FAT & PROTEIN METABOLISM

• Increase lipolysis and lipid mobilization with:

– Cholesterol– Triglicerides– Free fatty acids

– MUSCLE METABOLISM

• Modulates;

– Strength & velocity of contraction




– ELECTROLYTE BALANCE

• Low Thyroid hormones could induce hyponatremia

– VITAMIN METABOLISM

• Modulates vitamin consumption

– HEMATOPOIETIC SYSTEM

• Could induce anemiawww.freelivedoctor.com



– CARDIOVASCULAR SYSTEM• Hyperthyroidism, increases:

– Heart rate & myocardial strenght – Cardiac output– Peripheral resistances (Vasodilatation)– Oxygen consumption– Arterial pressure

• Hypothyroidism, reduces:– Heart rate & myocardial strenght– Cardiac output– Peripheral resistances (Vasodilatation)– Oxygen consumption– Arterial pressurewww.freelivedoctor.com


THYROID HORMONE EFFECTS– GASTROINTESTINAL SYSTEM

• Modulate bowel movements and absorption

– ENDOCRINE SYSTEM

• Modulates pituitary axis, affecting GH, ACTH, FSH, LH, so-on

– PREGNANCY

• Modulates growth rate and affects lactation



DIVIDED INTO:

– THYROTOXICOSIS (Hyperthyroidism)• Overproduction of thyroid hormones

– HYPOTHYROIDISM (Gland destruction)• Underproduction of thyroid hormones

– NEOPLASTIC PROCESSES• Beningn• Malignant


THYROID GLAND DISORDERS LABORATORY EVALUATION

TSH normal, practically excludes abnormality

– If TSH is abnormal, next step: Total & Free T4 & T3

- TSI (Thyroid Stimulating Ig)

- TPO (Thyroid Peroxidase Ab)

- Antimitochondrial Ab

- Serum Tg (Thyroglobulin)

- Radioiodine uptake & Thyroid scaning

- FNA, Fine-needle aspiration

- Thyroid ultrasoundwww.freelivedoctor.com


TSH High usually means Hypothyroidism

– Rare causes:• TSH-secreting pituitary tumor• Thyroid hormone resistance• Assay artifact

TSH low usually indicates Thyrotoxicosis

– Other causes• First trimester of pregnancy• After treatment of hyperthyroidism• Some medications (Esteroids-dopamine)



THYROTOXICOSIS: – is defined as the state of thyroid

hormone excesss

HYPERTHYROIDISM:

– is the result of excessive thyroid gland function



Abnormalities of Thyroid Hormones

– Thyrotoxicosis • Primary• Secondary• Without Hyperthyroidism• Exogenous or factitious

– Hypothyroidism• Primary• Secondary• Peripheral



Causes of Thyrotoxicosis:– Primary Hyperthyroidism

• Grave´s disease• Toxic Multinodular Goiter• Toxic adenoma• Functioning thyroid carcinoma

metastases• Activating mutation of TSH receptor• Struma ovary• Drugs: Iodine excess



Causes of Thyrotoxicosis:– Thyrotoxicosis without hyperthyroidism

• Subacute thyroiditis• Silent thyroiditis• Other causes of thyroid destruction:

– Amiodarone, radiation, infarction of an adenoma

• Exogenous/Factitia

– Secondary Hyperthyroidism• TSH-secreting pituitary adenoma• Thyroid hormone resistance syndrome• Chorionic Gonadotropin-secreting tumor• Gestational thyrotoxicosis



THYROTOXICOSIS

Symptoms:– Hyperactivity– Irritability– Dysphoria– Heat intolerance &

sweating– Palpitations– Fatigue & weakness– Weight loss with

increased appetite– Diarrhea– Polyuria– Sexual dysfunction

Signs:– Tachycardia– Atrial fibrillation– Tremor– Goiter– Warm, moist skin– Muscle weakness,

myopathy– Lid retraction or lag– Gynecomastia– * Exophtalmus– * Pretibial myxedema



Differential diagnosis:– Panic attacks

– Psychosis

– Mania

– Pheochromocytoma

– Hypoglycemia

– Occult malignancy



Treatment:

– Reducing thyroid hormone synthesis:• Antithyroid drugs (Methimazole, Propylthyouracil)• Radioiodine (131I)• Subtotal thyroidectomy

– Reducing Thyroid hormone effects:• Propranolol• Glucocorticoids• Benzodiazepines

– Reducing peripheral conversion of T4 to T3• Propylthyouracil• Glucocorticoids• Iodide (Large oral or IV dosage) (Wolf-Chaikoff effect)


THYROID GLAND DISORDERS Treatment: Special considerations:

– Thyrotoxic crisis or Thyroid storm:• It´s a life-threatening exacervation of thyrotoxicosis,

acompanied by fever, delirium, seizures, coma, vomiting, diarrhea, jaundice.

• Mortality rate reachs 30% even with treatment

• It´s usually precipitated by acute illness, such as:

– Stroke, infection,trauma, diabeic ketoacidosis, surgery, radioiodine treatment

• Propylthyouracil IV or Nasogastric tube• Radioiodine (131I)• Propranolol• Glucocorticoids• Benzodiazepines• Iodide (Large oral or IV dosage) (Wolf-Chaikoff effect)



HYPOTHYROIDISM– Primary

•Autoimmune (Hashimoto´s)•Iatrogenic Surgery or 131I•Drugs: amiodarone, lithium•Congenital (1 in 3000 to 4000)•Iodine defficiency•Infiltrative disorders



Hashimoto´s Thyroiditis or Goitrous thyroiditis

– Mean anual incidence:

• Women 4:1000 Men 1:1000• Risk factors; TPO antibodies (90%)

Japanese, previous history, high I intake• Average age: 60• Frequently associated to other

autoimmune disorders such as: AR, SLE, Sjogren´s so-on.

• Treatment: Levothyroxine



CONGENITAL HYPOTHYROIDISM

Prevalence: 1 in 3000 to 4000 newborns– Cause: Dysgenesis 85%– Dx: Blood screning (TSH &/or T4)

Treatment: – Supplemental Tx. With Levothyroxine is

“essential” for a normal C.N.S. Development and prevention of mental retardation



HYPOTHYROIDISM

– Secondary• Pituitary gland destruction• Isolated TSH deficiency• Bexarotene treatment• Hypothalamic disorders

– Peripheral:• Rare, familial tendency


HYPOTHYROIDISM

Symptoms:– Tiredness– Weakness– Dry skin Sexual

dysfunction– Dry skin– Hair loss– Difficulty

concentrating

Signs:– Bradycardia– Dry coarse skin– Puffy face, hands and

feet– Diffuse alopecia– Peripheral edema– Delayed tendon reflex

relaxation– Carpal tunel

syndrome– Serous cavity

effusions.


THYROID GLAND DISORDERS SPECIAL TREATMENT CONSIDERATIONS

Myxedema coma– Reduced level of consciousness, seizures– Hypotension/shock– Hypothermia– Hyponatremia

Usually in elderly hypothyroid pts.

Usually precipitated by intercurrent illnesses that impairs ventilation

It´s an Emergency with a high mortality rate

Treatment: Lyotironine(T3) or T4, Hydrocortisone, external warming, IV fluids


THYROID GLAND DISORDERS SPECIAL TREATMENT CONSIDERATIONS

Elderly patients

Coronary Artery Disease

Poor adrenal gland reserve

Childrens

Pregnancy

Emergency surgery (Non thyroid related)



THYROID GLAND NEOPLASIAS

Out of the focus of this lecture


THYROIDTHYROID

HyperthyroidismHyperthyroidism

• Thyrotoxicosis (most common cause)Thyrotoxicosis (most common cause)a) T3 and T4

• 3 most common causes:a) diffuse hyperplasia

i) Graves disease (~ 85% of cases)b) hyperfunctional multinodular goiterc) multifunctional adenoma of thyroid


• Clinicala) hypermetabolic state

i) skin warm, soft and flushedii) heat intolerantiii) sweatingiv) weight loss (despite appetite)v) cardiac earliest S & S HR, contractility, CO, cardiomegaly, arrhythmias ( A fib in older patients)vi) neuromuscular overactivity of

SNS causes tremors, anxiety, inability to concentrate, muscle weakness with muscle mass

(thyroid myopathy)


vii) Ocular wide, staring gaze and lid lag

- SNS overstimulation of levator palpebrae superiosis

- ptosis - true thyroid opthalmopathy seen

only in Graves disease viii) GI SNS hypermotility,

malabsorption and diarrheaix) Skeletal system bone

resorption, osteoporosisb) thyroid storm

i) abrupt onset of severe hyperthyroidism (Graves & SNS)


ii) febrile, HR (out of proportion to febrile response)

iii) is a medical emergency- death from cardiac arrhythmias

c) apathetic hyperthyroidismi) seen in elderlyii) age and other comorbidities blunt effects of excess thyroid hormone excess

- diagnosis during work up for unexplained weight loss or worsening

CV disease


d) Diagnosis i) measurement of serum TSH () in 1O

- in 2O TSH may be – or - “TRH stimulation test” excludes secondary hyperthyroidism

ii) T4 (sometimes T3)- in some cases, T4 may be - T3 may therefore be useful


Thyrotoxicosis results in an increase in metabolic rate. This may result in: Smooth, moist, warm skin Flushing of face and hands Overgrown nails (acropachy, clubbing), which may lift off the nail bed (onycholysis) Fine soft thinned scalp hair Generalized itching (pruritus) Urticaria Increased skin pigmentation “Pretibial myxedema”


HypothyroidismHypothyroidism• any defect causing thyroid hormone production

a) anywhere in hypothalamic-pituitary- thyroid axis

b) 1o are most common causei) “thyroprivic” (loss of parenchyma)ii) “goitrous” (due to TSH)

• Causesa) large surgical resectionb) ablation (radiation) of hyperthyroidism !c) autoimmune

i) most common cause of goitrous hypothyroidism


ii) most are due to Hashimoto thyroiditis (later)

d) drugsi) to thyroid secretionii) non thyroid conditions (lithium, -aminosalicylic acid)

e) inborn errors of thyroid metabolismi) uncommonii) any step of thyroid hormone

synthesis may be involved- e.g., “Pendred syndrome” failure of binding iodine in

thyroglobulin


f) thyroid hormone resistancei) receptor mutations

g) 2O hypothyroidismi) TSH deficiencyii) any of causes of hypopituitarism (frequently tumor). Other causes include: postpartum pituitary

necrosis, trauma, nonpituitary tumorsh) 3O (central) hypothyroidism

i) anything that interfere with hypothalamic-portal system

ii) inadequate TRH delivery


• CretinismCretinisma) hypothyroidism developing in

infancy/early childhoodi) severe mental retardationii) occurs in iodine deficient areas of world (i.e.,

Himalayas, inland China, Africa)iii) may also be sporadic, owing to

enzyme deficiencies thyroid hormone synthesis


b) clinical:i) impaired skeletal developmentii) impaired CNS development - inadequate maternal thyroid

hormone prior to fetal thyroid gland formation SEVERESEVERE mental retardation

- normal brain development if maternal thyroid deficiency occurs after

fetal thyroid gland development



• Myxedema (i.e., Gull disease)Myxedema (i.e., Gull disease)a) hypothyroidism developing in older child/adultb) slowing of physical and mental activity

i) generalized fatigueii) apathyiii) cold-intolerantiv) overweightv) CO

- shortness of breath- exercise capacity

vi) SNS activity - constipation- sweating


vii) skin pale, cool ( blood flow)viii) edema, puffy face, coarse hairix) broadening of facial featuresx) enlarged tonguexi) deepening of voice

c) clinical:i) TSH level most sensitive screening test

- in 1O (due to loss of feedback inhibition of TRH release)

- normal or not elevated in 2O or 3O hypothyroidism

- T4 in all forms of hypothyroidism




ThyroiditisThyroiditis• inflammation of thyroid

a) acute illness with thyroid painb) may not significantly affect thyroid function

• Types:a) Hashimoto thyroiditis (chronic

lymphocytic thyroiditis)i) gradual thyroid failure due to

autoimmune destruction of thyroidii) 45-65 yrsiii) 10:1 female predominanceiv) major cause of non endemic goiter in children


v) genetic component- patients with Turner syndrome

have circulating antithyroid Abvi) Clinical: 1) progressive depletion of

thyroid epithelial cells 2) replaced with mononuclear cells and fibrosis 3) comes to clinical attention as painless

enlargement of thyroid with some degree of

hypothyroidism 4) hypothyroidism progresses slowly 5) can be

preceeded by “hashitoxicosis” 6) patients at risk in developing other

autoimmune diseases 7) no CA risk


b) Subacute (granulomatous) thyroiditis [“aka De Quervain thyroiditis”]

i) occurs less often than Hashimotoii) 30-50 yrsiii) female preponderance 5:1iv) caused by viral infectionv) history of upper respiratory infection

just prior to onset of thyroiditisvi) seasonal incidence (summer peak)vii) acute or gradualviii) painful presentation, radiating to jaw, throat, ears: especially when swallowing !!


ix) inflammation and hyperthyroidism are transient

- followed by transient period of asymptomatic hypothyroidism

x) self limited diseasec) subacute lymphocytic (painless) thyroiditis

i) uncommonii) hyperthyroid presentation

- may present with any of signs of hyperthyroidism (no

opthalmopathy, as in Graves disease)


d) Riedel thyroiditisi) fibrosis of thyroid and neighboring

structuresii) presents as hard and fixed thyroid which clinically is similar to CA

e) Palpation thyroiditisi) vigorous clinical palpationii) thyroid function not affectediii) usually an incidental finding.


Graves diseaseGraves disease

• Most common cause of endogenous hyperthyroidism• Characteristics:

a) hyperthyroidismi) diffuse enlargement of thyroidii) lymphocytic infiltration

b) infiltrative ophthalmopathy i) with resultant exophthalmos

c) localized infiltrative dermopathyi) “pretibial myxedema”

- present in minority of cases !


Thyrotoxicosis results in an increase in metabolic rate. This may result in: Smooth, moist, warm skin Flushing of face and hands Overgrown nails (acropachy, clubbing), which may lift off the nail bed (onycholysis) Fine soft thinned scalp hair Generalised itching (pruritus) Urticaria Increased skin pigmentation “Pretibial myxedema”


• peak incidence 20-40• female preponderance (7:1)• familial link• Pathogenesis:Pathogenesis:

a) autoimmune disorderb) Ab against TSH receptor is central to disease

processc) retro-orbital connective tissue and ocular muscles are

increasedi) inflammatory edemaii) T-cell infiltrationiii) fatty infiltration iv) ECM accumulationv) these cause eye to bulge outward




d) Clinical:i) T3 and T4

ii) TSH

GoiterGoiter

Diffuse and multinodularDiffuse and multinodular• enlargement of the thyroid

a) most common manifestation of thyroid diseaseb) most often caused by dietary iodine deficiency

(i.e., impaired synthesis of thyroid hormone)i) compensatory rise in TSH


ii) hyperplasia and hypertrophy compensates for hormone deficiency (via TSH)

- result is euthyroideuthyroid stateiii) if response is inadequate

goitrous hypothyroid- enlargement is proportional to

degree and duration of thyroid hormone deficiency• Diffuse nontoxic goiterDiffuse nontoxic goiter

a) diffuse goiter without nodulesb) thyroid follicles filled with colloid

i) “colloid goiter”




c) two types:i) endemicii) sporadic

d) endemic goiterendemic goiter (<10% population)i) geographic area deficient in iodineii) mountainous areas of world

- Alps, Himalayas, Andes.iii) TSHiv) can result from ingestion of certain

“goitrogens”- cabbage, cauliflower, Brussels

sprouts, turnips, cassava- excessive calcium


e) Sporadic goiterSporadic goiteri) less frequent than endemicii) female preponderanceiii) peak incidence near puberty

• Multinodular goiterMultinodular goitera) recurrent hyperplasia/hypertrophyb) all simple nontoxic goiters evolve into multinodular

goitersc) produce the most extreme thyroid enlargements

i) often mistaken for neoplasmd) asymmetrically enlarged thyroid


e) small % of patients may develop a hyperfunctioning thyroid (nodule) resulting in a “toxic “toxic multinodular goiter”multinodular goiter”

i) Plummer syndrome is example- without dermopathy nor

ophthalmopathy (as in Graves)

• all goiters may cause “Mass Effects”a) dysphagiab) compression of large vesselsc) airway obstruction




Thyroid NeoplasmsThyroid NeoplasmsAdenomasAdenomas• discrete solitary masses• derived from follicular epithelium (i.e., “follicular adenomas”)

a) difficult to differentiate from a dominant nodule of follicular hyperplasia

b) NOT predecessors of malignancyc) mostly nonfunctional

i) small % produce hormones (thyrotoxicosis)

ii) hormones independent of TSH (thyroid “autonomy”). Similar to multinodular toxic goiter


• Pathogenesis:a) toxic adenoma

i) TSH receptor pathway is important signaling for hormone production

- overproduction of cAMPii) “hot” nodules iodine uptake

b) usually present as unilateral painless massc) take up less radioactive iodine compared to normal thyroid

parenchymal cellsi) “cold” nodulesii) ~10% of cold nodules malignantiii) “hot” nodules rarely malignant

d) biopsy is “gold” standard for diagnosis



e) do not recur nor metastasize • other benign tumors

a) cystsi) usually represent cystic degeneration of

thyroid follicular adenomab) lipomasc) hemangiomasd) dermoid cystse) teratomas (mainly in infants)


• Thyroid Cancer typically appears as a "cold nodule". That is to say, it appears as a white area or defect in an otherwise black thyroid. A "cold" area is NOT necessarily cancer. Indeed, most "cold nodules" are benign! Ultrasound, perhaps followed by biopsy, often plays an important role in differentiation


Thyroid CarcinomasThyroid Carcinomas

• relatively uncommon in USA• most appear in adults

a) papillary CA may present in childhood• female predominance (early and middle adult)

a) childhood and late adulthood have equal gender distribution

• most CA are well differentiated:a) papillary CA (~80% of cases)b) follicular CA ( ~15% of cases)c) medullary CA (~5% of cases)d) anaplastic CA (< 5% of cases)


• genetic and environmental factors implicateda) genetic factors seen in both familial and nonfamilial

(sporadic) forms of CAi) familial medullary CA most

inherited of thyroid CAii) papillary and follicular familial CA are

very rare !!b) exposure to ionizing radiation during first exposure to ionizing radiation during first 2 decades 2 decades

of life is one of the most of life is one of the most important factors predisposing important factors predisposing one to one to thyroid cancer thyroid cancer


i) in past, radiation of head and in past, radiation of head and neck in children for a variety of neck in children for a variety of problems has led problems has led to ~ 10% to ~ 10% developing thyroid carcinoma developing thyroid carcinoma

ii) atomic bomb survivors as well as atomic bomb survivors as well as those those survivors following survivors following Chernobyl incident have Chernobyl incident have thyroid thyroid carcinoma carcinoma

- type is type is papillary carcinomac) pre-existing thyroid disease pre-existing thyroid disease

i) multi-nodular goiter have multi-nodular goiter have predisposition to develop predisposition to develop carcinoma carcinoma

due to areas of due to areas of iodine iodine- type is follicular carcinoma


• Papillary CarcinomaPapillary Carcinomaa) most common of thyroid carcinoma most common of thyroid carcinomab) any age any agec) vast majority of carcinoma associated vast majority of carcinoma associated with ionizing with ionizing

radiation exposureradiation exposured) solitary or multi-focal nodules solitary or multi-focal nodulese) are non-functional tumors are non-functional tumors

i) painless masses painless massesii) within thyroid or metastasis to within thyroid or metastasis to

cervical lymph nodescervical lymph nodes


• Follicular CarcinomaFollicular Carcinomaa) second most common form of thyroid second most common form of thyroid carcinoma carcinomab) incidence in areas of dietary iodine incidence in areas of dietary iodine deficiency deficiencyc) do do not arise from pre-existing adenomasnot arise from pre-existing adenomasd) present most often as solitary nodules present most often as solitary nodules with no iodine with no iodine

uptake (“cold nodules”)uptake (“cold nodules”)e) metastasize via blood to lungs, bone and metastasize via blood to lungs, bone and liver liverf) unlike papillary carcinoma, regional nodal unlike papillary carcinoma, regional nodal

involvement is uncommoninvolvement is uncommon


• Medullary CarcinomaMedullary Carcinomaa) secrete calcitonin from “C” cells secrete calcitonin from “C” cells

i) calcitonin important diagnostic calcitonin important diagnostic measurement as well as a follow-up measurement as well as a follow-up following treatment following treatment

b) may arise as solitary nodule or multiple may arise as solitary nodule or multiple lesions lesionsc) ”C” cell hyperplasia ”C” cell hyperplasia

• Anaplastic CarcinomaAnaplastic Carcinomaa) most aggressive thyroid neoplasms most aggressive thyroid neoplasmsb) predominantly in elderly patients predominantly in elderly patients

i) areas with endemic goiter areas with endemic goiterc) death in < 1 year ( compromise of neck) death in < 1 year ( compromise of neck)d) distant metastasis is common distant metastasis is common


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Diseases of thyroid gland