Thyroid functions and disorders presentation

THYROID FUNCTIONS AND DISORDERS

By

Dr. Basil, B. C – MBBS (Nig),Department of Chemical Pathology/Metabolic Medicine,

Benue State University Teaching Hospital, Makurdi.February 2016.

OUTLINE:• Introduction• Anatomy• Hormone synthesis/secretion• Metabolism/Mechanism of action• Functions and Control• Disorders and Biochemical findings• Biochemical Screening and Evaluation of thyroid

disease• Treatment of Thyroidal Diseases• Reference.

INTRODUCTION:

• The thyroid gland – largest single endocrine gland in the body (15 – 20g)

• Produces the Thyroid hormones and Calcitonin

• Thyroid hormones are critical in regulating body metabolism, neurologic, developmental and other body functions

• Calcitonin involved in calcium homeostasis – see calcium and phosphate disorders.

ANATOMY

• Consist of 2 lobes and a central isthmus – anterior to the trachea (shaped like a bow-tie)

• Posteriorly – parathyroid glands• Originate from Ratke’s pouch at the base of the

tongue at 4-8wks IUL, and secretes hormones by 11wk – critical to neurologic development

• Consist of many small spherical follicles (functional unit) surrounded by basement membrane, containing colloid and interspersed by para-follicular C cells

HORMONE SYNTHESIS / SECRETION

• Thyroid hormone synthesis includes the following steps:– Iodide (I-) trapping via Na-I- symporter (active

transport) by follicular cells (Rate limiting step)– Diffusion of iodide to the apex of the cell and

transport into the colloid– Oxidation of inorganic iodide to iodine (by

thyroperoxidase) and incorporation of iodine into tyrosine residues within the thyroglobulin molecule in the colloid


• Steps contd:– Combination of two DIT molecules to form T4 or

of MIT and DIT to form T3– Uptake of thyroglobulin from the colloid into the

follicular cell by endocytosis, fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4 and T3

– Release of T4 and T3 into the circulation– MIT and DIT are split into iodine and tyrosine, and

recycled


• T4 & T3 Circulate predominantly (>99%) bound to serum proteins– Thyroxine binding globulin (TBG) – 75%– Thyroxine binding prealbumin (TBPA) – 15%– Albumin – 10%

• The bound hormone is not biologically active• Only 0.04% of T4 and 0.4% of T3 - free• Changes in the concentration of serum binding

proteins alter the total, but not the free hormone levels

STRUCTURE OF THYROID HORMONES

METABOLISM• 100nm of T4, 5nm each T3 and rT3 secreted daily• T3 – active form; T4 – prehormone; rT3 –

metabolically inactive; Thyroglobulin – prohormone.

• T4 >> T3: outer ring 5’monodeiodination (80% of T3) by iodothyronine deiodinase (3 types) – inhibited by Propylthiourasil etc

• Inner ring deiodination >> rT3 (3,3’,5’ triiodothyronine)

• 10% T4 cleared: 80% deiodinated, 20% glucuronidation in liver and sulfation in liver and kidneys

• Half-life: T4= 7days, T3=1 day

MECHANISM OF ACTION

• T4 dissociates with its carrier protein and diffuse though cellular membrane into the cytosol where it is converted to T3 by deiodinase enzyme

• T3 binds with Nuclear receptor protein >> Hormone-Receptor protein complex >> binds to the hormone receptor element (or Thyroid Response Element) on the DNA >> initiation of transcription and protein synthesis

MECHANISM OF ACTION

FUNCTIONS

• General metabolism:– Increase the metabolic rate and oxygen consumption

of most of tissues of the body (exceptions include testes, uterus, lymph nodes, anterior pituitary)

– Increase synthesis and activity of many intracellular enzymes e.g. Na+-K+ ATPase utilizes energy, increase heat production

– Increase the size, number & activity of mitochondria >> increase the rate of formation of ATP to energise cellular function

FUNCTIONS

• Growth and Development:– Essential for normal growth of soft tissue and

skeleton– Required for production & action of growth

hormones and IGF• Respiration:– Increased respiration due to increased rate– Dissociation of oxygen from hemoglobin by

increasing the amount of 2,3 DPG in RBC

FUNCTIONS

• Cardiovascular:– Increase number & affinity of beta-1, adrenergic

receptors in the heart, also increase its sensitivity to catecholamine

– Increases rate of blood flow in the skin for heat elimination

– Increased cardiac output >> ↑systolic BP, but ↓ diastolic blood pressure thus >> ↑ pulse pressure

FUNCTIONS

• Gastrointestinal:– Increase secretion of digestive juices and motility

>> increase appetite and food intake– Necessary for the hepatic conversion of carotene

to Vit.A, so if thyroid hormones are decreased, carotenaemia result

• Reproduction:– Essential for normal menstrual cycles and fertility– Increase milk secretion in lactating women

FUNCTIONS

• Nervous System:– Promotes growth and development of the brain

(fetal life & for the first few years)– Essential for normal myelination & development

of the nervous system in infant– Increased response of the brain to catecholamines

& increases activation of RAS

FUNCTIONS

• Carbohydrate metabolism:– Increases the rate of absorption of CHO from GIT,

thus blood glucose level increases after meal but fall again as rate of glucose utilization is also increased

– Enhance gluconeogenesis & glycolysis– Increases cell metabolic enzymes acting on CHO

FUNCTIONS

• Protein metabolism:– Small doses of thyroid hormone increase the rate

of formation of proteins by the ribosomes– It increase RNA synthesis by the genes– Large doses of thyroid hormone lead to excess

catabolism of muscle protein

FUNCTIONS

• Lipid metabolism:– All aspects of fat metabolism increased– Thyroid hormone accelerates the oxidation of

fatty acids by the cells– Lowers level of cholesterol, phospholipid &

tryglycerides in the blood– Stimulate formation of LDL receptors

CONTROL OF THYROID FUNCTION


• TRH >> (+)TSH >> (+)T4/T3 >> (-)TSH/TRH• T4 released by the thyroid is mostly converted

to T3 by the liver and kidney by type 1 iodothyronine 5’-deiodinase

• Type 2 iodothyronine 5’-deiodinase found in the brain and pituitary maintain constant levels of T3 in the CNS


• TSH/Thyrotropin – Primary Regulation– Glycoprotein hormone– Made up two units α and β (2 different

chromosomes)– α subunit is identical to that of LH, FSH, hCG– β subunit confers specificity– t½ is 60 minutes– Acts via the TSH receptor – G protein coupled (7

transmembrane domain)


• Actions of TSH:– Increased proteolysis of the thyroglobulin (occurs

within minutes)– Increased activity of the iodide pump– Increased iodination of tyrosine– Increased size and increased secretory activity of

the thyroid cells– Increased number of thyroid cells

DISORDERS OF THYROID • Hyper-functioning states– Overt– Subclinical

• Hypo-functioning states– Overt– Subclinical

• Others– Inflammatory– Neoplastic disease– Non-thyroidal illnesses (Euthyroid Sick Syndrome)– Euthyroid hyperthyroxinaemia

HYPER-FUNCTIONING STATES:

• Definitions:– Thyrotoxicosis: Hypermetabolic state produced

due an excess of thyroid hormones– Hyperthyroidism: Hypermetabolic state due to an

excessive activity of the thyroid gland– Hyperthyroidism is a cause of thyrotoxicosis but

Thyrotoxicosis is not always as a result of hyperthyroidism

• Women are more prone to develop hyper-thyroidism than men

Causes:

• Primary hyperthyroidism:– Graves’ disease (Diffuse toxic non-nodular goitre)– Toxic multinodular goiter(Plummer disease)– Toxic adenoma– Functioning thyroid carcinoma metastases– Activating mutation of the TSH receptor– Activating mutation of G (McCune-Albright syndrome)– Struma ovarii– Drugs: iodine excess (Jod-Basedow phenomenon)

Causes:

• Thyrotoxicosis without Hyperthyroidism:– Subacute thyroiditis– Silent thyroiditis– Other causes of thyroid destruction: amiodarone,

radiation, infarction of adenoma– Ingestion of excess thyroid hormone

(thyrotoxicosis factitia)

Causes:

• Secondary hyperthyroidism:– TSH-secreting pituitary adenoma– Chorionic gonadotropin-secreting tumours e.g

Trophoblastic tumor (Hydatidform mole)– Gestational thyrotoxicosis

HYPER-FUNCTIONING STATES:• Grave’s disease:– accounts for more than 60% of all thyrotoxicosis– diffuse glandular hyperplasia– 10 times more common in women– Autoimmune basis: thyroid stimulating

immunoglobulins (TSI) that bind to the TSH-Receptor• Toxic Adenoma:– solitary hyper-functioning nodules– acquired somatic activating mutations in the TSH-R.

which induce constitutive receptor coupling to Gs– clinical features are milder than above

HYPER-FUNCTIONING STATES:

• Multi-nodular goiter:– multiple nodules, maybe polyclonal or monoclonal in

origin– usually do not have TSH-R mutations– may present with subclinical or mild thyrotoxicosis

• Subacute Thyroiditis (De Quervain’s, Bacterial, Granulomatous, or Viral thyroiditis):– follicular destruction releases thyroid hormones– later phase may be hypothyroid, with depletion of

thyroid hormones

Biochemical findings:• In primary hyperthyroidism – T4 and T3 are elevated,

while TSH is suppressed to undetectable concentrations• Secondary hyperthyroidism is characterized by elevated

levels of TSH, free T4 and/or free T3 levels.• T3 concentration is often elevated to a greater degree

than is T4 in the early stages of Graves’ disease and in patients with T3 thyrotoxicosis (solitary or multinodular toxic goiters)

• In subclinical hyperthyroidism, there is normal concentration of serum T3 and FT4 and persistently suppressed serum TSH

HYPOFUNCTIONING STATES

• Primary Hypothyroidism:– Autoimmune hypothyroidism: Hashimoto’s

thyroiditis, atrophic thyroiditis– Iatrogenic: 131I treatment, subtotal or total

thyroidectomy,– External irradiation of neck for lymphoma or cancer– Drugs: antithyroid drugs, amiodarone, lithium– Congenital hypothyroidism– Iodine deficiency– Infiltrative disorders

Causes:

• Transient Hypothyroidism:– Silent thyroiditis– Subacute thyroiditis– Withdrawal of thyroxine treatment in individual

with an intact thyroid– After 131I treatment or subtotal thyroidectomy for

Graves’ disease

Causes:

• Secondary hypothyroidsm:– Hypopituitarism: tumours, pituitary surgery or

irradiation,– Infiltrative disorders, Sheehan’s syndrome, trauma– Isolated TSH deficiency or inactivity– Hypothalamic disease: tumours, trauma, infiltrative

disorders,– Idiopathic– Drugs: Dopamine, Corticosteroids– Congenital TRH deficiency (rare)

HYPOFUNCTIONING STATES• Iodine deficiency:– Commonest cause of worldwide– Responsible for endemic goiter and cretinism (mental and

growth retardation in children)– Incidence also impacted by thiocynates in cassava and

selenium deficiency• Hashimoto’s thyroiditis:– Autoimmune based disease– Destruction of thyroid cell by CD8+ cytotoxic T cells– Antibody markers include Anti TPO, TG and TSH-R blocking

Ab– Clinical course: subclinical (or mild) to clinical (or overt)

HYPOFUNCTIONING STATES

• Congenital hypothyroidism– thyroid agenesis– inborn errors of thyroid hormone synthesis– TSH-R mediated

• Iatrogenic– Radio iodine therapy– Subtotal/total thyroidectomy

• Pituitary disease (Secondary hypothyroidism)

HYPOFUNCTIONING STATE

• Peripheral Resistance to Thyroid Hormones:– The most common cause of the syndrome are

mutations of the β (beta) form (THRB gene) of the thyroid hormone receptor

– Mutations in MCT8 and SECISBP2 have also been associated with this condition

– Also referred to as impaired sensitivity to thyroid hormone

HYPOFUNCTIONING STATES• Myxedema is a severe form of hypothyroidism in

which there is accumulation of mucopolysacchrides in the skin and other tissues, leading to thickening of facial features and a doughy induration of the skin

• Cretinism is the term used to describe severe hypothyroidism that develops in the newborn period

• Congenital hypothyroidism: may be as a result of a complete absence of thyroid gland (athyreosis) or defects in thyroid hormone synthesis, which can lead to irreversible neurological damage without early treatment

Biochemical Findings:

• Primary hypothyroidism:– Low T4 and T3 lead to pituitary hypersecretion

evidenced by elevated serum TSH concentration an important finding particularly in early detection of thyroid failure

– In mild or subclinical cases, thyroid hormone concentrations remain within the reference range but TSH is elevated.

– Presence of a circulating autoantibodies especially TPOAb in serum

Biochemical Findings:

• Secondary hypothyroidism:– Serum concentration of thyroid hormone is low,

but TSH is either low or within the healthy reference interval

• Peripheral resistance to thyroid hormones:– T4 and T3 are elevated but TSH is not suppressed

(or not as suppressed as expected)

OTHER DISORDERS

• Non-Thyroidal Illnesses/Sick Euthyroid Syndrome– Any acute or chronic severe illness causing

abnormalities in circulating TSH or thyroid hormone levels in the absence of underlying thyroid disease.

– Reduced T4 ->T3 conversion but normal/increased rT3– Importance is because of misleading information from

thyroid testing during periods of acute illness.– Unless a thyroid disorder is strongly suspected, routine

testing of thyroid function should be avoided in acutely ill patients

OTHER DISORDERS

• Biochemical Findings in Non-Thyroidal Illness/ Euthyrois sick syndrome:– Low serum T3 level– High serum rT3 level– Normal or Low serum T4 levels– If serum TBG levels are low, serum T4 would be

low– Serum TSH levels are usually normal, but may

show mild depression during acute phase and mild elevation during recovery phase

OTHER DISORDERSThyroid Malignancies – 4 types:• Papillary carcinoma (PC):– Well differentiated, very good prognosis; 90% 20 year

survival post treatment.•Follicular carcinoma (FC):– Well differentiated, very good prognosis; 90% 20 year

survival post treatment.•Medullary carcinoma of thyroid (MCT):– Poorly differntiated. 50% 10 year survival– High calcitonin is a marker

•Anaplastic carcinoma:– Poorly differentiated. Mortality approaches 100%

OTHER DISORDERS

Thyroid Neoplasia:•Solitary Thyroid Nodules:– As many as 50% of these are benign– Occasionally, thyroid nodules can take on

characteristics of malignancy and require either a needle biopsy or surgical excision

OTHER DISORDERS

• Biochemical findings in Euthyroid Hyper-thyroxinaemia:– Serum total T4 level is high– Serum T3, TSH and TRH response are normal

• FT4 level compares well with the functional condition of the thyroid than Total T4

• Causes: Bisalbuninaemia, increase oestrogen, pregnancy, liver disease, acutely hospitalized psychiatric pxt, familial dysalbuminaemia

BIOCHEMICAL SCREENING AND EVALUATION OF THYROID DISEASE

• NEONATAL SCREENING:• When to screen:– Normal hospital delivery at term – (filter-paper

collection ideally at 2 – 4days of age or at the time of discharge)

– NICU/Preterm home birth – (within 7days of birth)– Maternal history of Thyroid medication/family

history of Congenital hypothyroidism – (cord blood for screening)

BIOCHEMICAL SCREENINGType of Screening:•Primary TSH + Backup T4– May miss:

• TBG deficiency• Hypothalamic-pituitary Hypothyroidism• Hypothyroxinemia with delayed TSH elevation

– For better sensitivity – use sensitive TSH assay and age adjusted TSH cutoff (20 – 25mU/L at 24hr of age)

•Primary T4 + Backup TSH:– Will miss delayed TSH elevation with initial normal T4

•Primary T4 and TSH:– Ideal screening approach

BIOCHEMICAL SCREENING

EVALUATION OF THYROID DISEASE• EVALUATION OF THYROID DISEASE:• TSH:– The most useful test for assessing thyroid function– Used to monitor and adjust thyroid hormone

replacement therapy as well as screen for both hyperthyroidism and hypothyroidism

– Have been deployed in the management of subclinical thyroid disease

– For pregnant women with previously diagnosed hypothyroidism, serum TSH levels should be measured every 3-4 weeks during the first half of pregnancy and every 6-10 weeks thereafter

EVALUATION OF THYROID DISEASE Low free T4 Normal free T4 High free t4

Low TSH

Secondary hypothyroidism Severe NTI

Subclinical hyperthyroidismNTI

Hyperthyroidism

Normal TSH

Secondary hypothyroidism Severe NTI

Normal ArtifactPituitary hyperthyroidismLab draw within 6hrs of thyroxine dose

High TSH

Primary hypothyroidism

Subclinical Hypothyroidism

Test artifactPituitary hyperthyroidismThyroid hormone resistance

EVALUATION OF THYROID DISEASE

• Thyroglobulin:– Ideal tumor marker for thyroid cancer patients and its

detection is a proof of thyroid tissue either benign or malignant

– The accuracy of the assay is primarily dependent on the specificity of the antibody used and the absence of antithyroglobulin autoantibodies which interfere with measurements

– Its prevalence is noted to be 3% of the general population, 12 – 30% of patients with Graves’ disease, and 35 – 60% with Autoimmune hypothyroidism


• Thyroid Autoimmunity:– In autoimmune thyroid disease, antibodies are

directed at thyroid tissue with variable responses– In Graves’ disease (the most common cause of

hyperthyroidism), the antibody is directed to the TSH receptor, stimulating it and leading to growth of the thyroid gland and production of an excess amount of thyroid hormone

– Tests for TSH receptor antibodies detect any antibody (stimulating or blocking) against TSH receptor


• Thyroid Autoimmunity – contd– Both stimulating and blocking antibody assays will

be positive in most patient with Graves’ disease– In Hashimoto’s thyroiditis, Thyroid peroxidase

antibody mediate decreased thyroid hormone production


• Urinary Iodine measurements– Iodine essential for normal thyroid gland function– Iodine deficiency responsible for endemic goitre

and cretinism– Majority of ingested iodine is excreted in the urine– Only reflects recent dietary pattern– Major use is for epidemiologic purposes– Use 24 hour urine sample


• OTHER TOOLS:– Nuclear Medicine Evaluation – RAIU Assay• High uptake – metabolically active gland• Concurrent TSH assay done• Low uptake -

– Thyroid Ultrasound – detects very small nodules– Fine-Needle Aspiration Biopsy – first step and

most accurate tool in the evaluation of thyroid nodules

TREATMENT OF THYROIDAL DISEASESHYPERTHYROIDISM:•Use of beta-blockers for symptomatic relief:– To be commenced after oral rehydration if necessary, and

avoided in known asthmatics– If beta-blockers are contraindicated or poorly tolerated,

calcium channel blockers (verapramil or diltiazem) can be administered

•Use of anti-thyroid drugs(e.g Carbimazole, Methimazole, Propylthiouracil):– Carbimazole, initial dose 30-40mg/day; maintainance 15-20

mg/day– Preferred in younger age group, especially children– More useful in Small diffuse gland and mild disease and in

cases of expected remission, especially immunological background

– Therapy needs to be continued up to 12 months. Remission rate is 40-50%

TREATMENT OF THYROIDAL DISEASES• Use of radioactive iodine-131 (131 I) therapy:– 5-7 mCi single dose 131l therapy; 1/3 will require a second

dose– Recommended for more than 35 years of age and in cases of

Severe thyrotoxicosis, Systemic illness that prevents other methods of treatment and Recurrence after antithyroid drugs, surgery or radioablation

– There is minimal risk involved; symptoms abate in 3 weeks to 3 months

• Surgical approach (thyroidectomy):– Subtotal thyroidectomy (leave 2-3 g of tissue; prepare

suitably with antithyroid drugs) is preferred in cases where there is• Large size of gland• Multinodularity• Pressure symptoms• Retrosternal goiter

TREATMENT OF THYROIDAL DISEASES• In thyroid crisis, treatment has to be aggressive:– Propranolol 1-2 mg slowly IV or 40-80 mg orally is the first

step. This can be repeated 6 hourly. – Appropriate sedation by phenobarbitone may relieve

anxiety. Barbiturates retard the peripheral deiodination of the hormone

– Thyroid hormone release can be inhibited by IV iodine in the form of sodium iodide 1 g IV in 24 hours or by oral Lugol’s iodine 5 drops every 6 hours. Drugs such as amiodarone can be used as well.

– This is followed by thionamide or thiouracil administration in regular dosage.

– Corticosteroids (especially dexamethasone) are indicated if there is slightest suspicion of limitation of the adrenocortical reserve

– Fluid and electrolyte balance should be adequately corrected.

TREATMENT OF THYROIDAL DISEASESHYPOTHYROIDISM:•Use of Levothyroxine (LT4) for Thyroid hormone replacement – treatment of choice:– Started as full replacement in young individuals but in

the elderly and those with IHD, treatment with quarter to half the required dose is initiated and raised gradually over 4-6wks

– For mild to moderate conditions, starting dose is about 50-75µg/day

– Clinical benefits begin btw 3-5days and level off after 4-6wks but TSH take several months to get to target range due to delayed re-adaptation of the hypothalamic-pituitary axis

– In central hypothyroidism, T4 levels are used to guide treatment instead of TSH levels

TREATMENT OF THYROIDAL DISEASES• In pregnant women with hypothyroidism, the LT4 dose

should be adjusted so as to keep the serum TSH below 2.5 mIU/L. TSH and free T4 levels should be measured 3-4 weeks after every dosage adjustment.

• In subclinical hypothyroidism, guidelines from the American Association of Clinical Endocrinologists (AACE) recommend treatment in patients with TSH levels higher than 10 mIU/L and in patients with TSH levels of 5-10 mIU/L in conjunction with goiter or positive anti-TPO antibodies; – These patients have the highest rates of progression to overt

hypothyroidism.– An initial LT4 dosage of 50-75 µg/day can be used, which can

be titrated every 6-8 weeks to achieve a target TSH of between 0.3 and 3 mIU/L

TREATMENT OF THYROIDAL DISEASES

• In patients with myxedema coma: – Give 4 µg of LT4 per kilogram of lean body weight

(approximately 200-250 µg) as an IV bolus in a single or divided dose, depending on the patient’s risk of cardiac disease

– 24 hours later, give 100 µg IV– Subsequently, give 50 µg/day IV, along with stress

doses of IV glucocorticoid• Adjust the dosage on the basis of clinical and

laboratory findings

REFERENCES• Teitz Textbook of Clinical Chemistry and Molecular

Diagnostics; 5th ed., by Burtis et al• Clinical Chemistry – Principles, Techniques and

Correlations, 7th ed., by Micheal L. Bishop et al.• Thyroid Function and Disorders; Abuja Revision Course,

NPMCN, Feb 2016, by Christian Ogoegbunem Isichie.• Robbins and Cotran - Pathologic Basis of Disease 7th ed., by

Kumar et al.• Bolarin’s Aids to Chemical Pathology, New ed., by Debayo

M. Bolarin• Clinical Chemistry and Metabolic Medicine, 7th ed., by

Martin Crook.• Clinical Chemistry in Diagnosis and Treatment, 6th ed., by

Philip D. Mayne

Thyroid functions and disorders presentation

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