Thyroid disorders

Dr. Sujay Patil

Thyroid gland

– serves a cosmetic function of giving grace to the contour of the neck ”

- Wharton (1656)

History• Described by Galen• Wharton (1656) - glandulae thyroideae• Hyperthyroidism – Parry 1825

- Graves 1835 - Basedow 1840

• Murray (1891) - treated case of hypothyroidism• Magnus Levy (1895) – effect of thyroid on metabolic rate• Kendell(1915) – isolated thyroxine in crystalline form • Harrington and Barger (1927) - synthesized thyroxine

Introduction

• Thyroid gland – a large gland in neck, secrete hormones that regulate growth and metabolism.

• Weight – 25 -35 gm.

• Basic unit of thyroid gland – thyroid follicle

• Follicular cells secrete T3 and T4 & Parafollicular cells (C- cells) secrete Calcitonin under TSH influence.

Chemistry and Synthesis

• T3 & T4 – iodine containing derivatives of thyronine

• Thyroxine (T4) – 3,5,3’,5’ tetroidothyronine (T3) – 3,5,3’ tridothyronine

• Thyroid hormones are stored in thyroid follicle as part of TGB molecule

Steps involved in Synthesis

1) Iodide trap by follicular cells Trap with help of N+/I- Symporter in to follicular cells

2) Oxidation & Iodination

Pendrin transport Iodide into cytosol

Iodide oxidized Thyroid peroxidase Iodinium(I+) H2O2 Hypoiodus acid (HOI) Enzyme linked hypoiodate (E-OI)

These combine with tyrosil residues of TGB to form MIT & DIT.

3) Coupling

Iodinated tyrosil residues couple together under thyroid peroxidase enzyme influence.

MIT + DIT – T3DIT + DIT – T4

Oxidation and coupling both under TSH influence

4) Storage & Release Iodinated Tyrosil & Thyronil reisdues remain as colloid & later transported into interior of cells by endocytosis. Lysosomes engulf colloid and acted upon by proteolytic enzymes. TSH influence present.

Free T3 & T4 released, MIT & DIT deiodinated.

5) Transport of T3 & T4 into plasma & their protein binding

TBG – 75 % T3,T4 TBPA – 15 – 20 % TBA – 12 – 15 %

Free T3 – 0.5% Free T4 – 0.05%

6) Peripheral conversion of T4 to T3

Liver & kidney convert T4 T3

Target tissue need T3 for metabolic action

T4 DID – 1 T3 (Active) Propylthiouracil inhibit DID -1 DID – 2 Amiodarone inhibit DID – 1 & 2T4 DID – 1 rT3 (Inactive) DID – 3

Transport, Metabolism & Excretion

• Same as discussed

• Glucoronide / sulfate conjugation of hormones & deiodinated products.

• Liver (primary), kidney & salivary glands are other metabolic sites.

• Conjugated metabolites excrete in bile followed by deconjugation in intestines & again reabsorbed (Enterohepatic circulation).

• T ½ T4 – 6-7 days T3 – 1-2 days

Regulation of Thyroid hormone Secretion

• Action of TRH on pitutary & TSH on thyroid mediated by enhanced cAMP synthesis.

• Proterelin – another synthetic tripeptide acting like TRH.

Mechanism of action of Thyroid Hormone

• T3, T4 penetrate by active transport in cell & bind to thyroid hormone receptor (TR).

• Usually TR is in inactivated state & is bound to thyroid response element (TRE) along with corepressors keeping gene transcription suppressed.

• T3 bind to TR binding leads to heterodimerization with Retionoid X Receptor (RXR). Conformational change releasing corepressor and binding co-activator.

• Induces gene transcription, pattern specific mRNA, protein synthesis & metabolic effects.

Physiological Actions

1. Growth & development

Mainly Milestone & CNS development

2. Intermediary metabolism

Lipids – enhance lipolysis (catecholamine's, lipolytic hormones)

Carbohydrate – Increased glucose utilization by cells Glycogenolysis & Gluconeogenesis Increased absorption Diabetic like state

Proteins – Prolong action of T3 results in – ve nitrogen balance & tissue wasting (Weight loss).

3. Calorigeneis Uncoupling of oxidative phosphorylation release excess energy & heat.

4. CVS

Increased peripheral demand, contractility & CO (Hyper dynamic state).

Up regulate Beta receptors.

5. Nervous system

Behavioural & functional effects.

6. Skeletal Muscle

Low – Weak & flabby muscles, High - tone, tremor

7. GIT

Low - GI motility – Constipation

High - GI motility – Diarrhoea

8. Kidney

Increased urine frequency

9. Haemopoesis

Facilitate erythropoiesis. If low – anemia occurs.

10. Reproduction

Normal pregnancy & lactation. If Low – fertility impaired.

Thyroid Disorders

Hypothyroidism

a syndrome due to deficiency of thyroid hormones.

Irreversible mental retardation in children

More common in women.

1. Cretinism

Hypothyroidism during foetal life

Mental retardation, pot bellied, yellow skin dwarfs (Cretins).

More weight due to decreased BMR

Due to Iodine deficiency OR presence of TSH receptor – blocking antibodies.

Insulin resistance

Endemic cretinism – mother is iodine deficient

Rx • Initial daily dose - L-T4 10–15 mcg/kg

• Doses adjusted at 4–6-week intervals during first 6 months, 2-month intervals during the 6–18-month, then 3–6-month intervals

• Goal - maintain serum free T4 levels in the upper half of the normal range, or slightly above the normal range, with a normal TSH.

2. Myxoedema

Hypothyroidism during adult years.

Antibodies against thyroid peroxidase or thyroglobulin

Severe hypothyroidism in which there is accumulation of hydrophilic mucopolysaccharides in the skin and other tissues making face to swell and look puffy.

Increased deposition of glycosamino glycan's.

Common in women.

Rx• Supportive care and treatment of the precipitating cause L-T4 - loading dose 200–300 mcg - 24 hours later 100 mcg IV daily maintenance dose

• Add - L-T3 - 10 mcg IV 8 hourly ( in young pts.)

• Overly aggressive treatment – may be associated with increased mortality

3. Myxoedema Coma

Medical emergency

Uncommon but life threatening form of untreated hypothyroidism with physiological decompensation.

Occurs in patients with long standing hypothyroidism.

Precipitated by a climate induced hypothermia, infection, drug therapy and other systemic conditions

Progressive mental deterioration

Increased mortality risk

Rapid Rx required

Ventilate pt. if respiratory acidosis is significant.

Immediate IV levothyroxine given Loading dose of 500 - 800mcg followed by 50 – 100mcg daily.

Hydrocortisone 100 mg IV

Treatment of associated infection.

Correction of hyponatremia with saline.

Correction of hypoglycemia with IV dextrose.

4. Hashimoto’s thyroiditis

Immune reaction against TG

Autoimmune destruction of thyroid gland

Low T3, T4 & TSH

Rx – L-thyroxine Mild: 50 -75 µg/day Moderate & severe: 1.6 µg/kg body weight.

5. Non – toxic goitre

Endemic or Sporadic

Endemic – deficiency of iodine

Sporadic – Defect in hormone synthesis

Low T3, T4 Increased TSH Thyroid gland enlargement more iodide trapped increased T3 synthesis demands met patient euthyroid.

Rx – 150 – 200 µg of iodine daily ( iodized edible salt)

6. Thyroid nodule

Excess TSH release causes a thyroid nodule

Rx – T4 therapy 2.6 µg/kg single oral daily dose

Stop Rx if no reduction in 6 months

7. Papillary Carcinoma of Thyroid

Excess TSH

Rx – T4 therapy 2.5 – 3.5 µg/kg/day

8. Hypothyroidism during pregnancy

Maternal TBG levels, so less free T4. Rx – L – thyroxine on demand

Hyperthyroidism

Hyperthyroidism - T3, T4 production

Thyrotoxicosis - ingestion of thyroid hormones

1. Grave’s disease

Most common

Autoimmune disorder

Pt. produce TSH receptor stimulating Ab’s mimicking action of TSH, no negative feedback.

T3, T4, TSH – R Ab’s & TSH is low.

Enlarged thyroid, exophthalmos are evident.

Rx

• Immediate control: Propranolol 40mg/6hr orally.

• Long term control: Anti thyroid drugs – Carbimazole 15mg TDS initially and then reducing it to 5mg TDS for 12-18 months.

• Radio iodine ablation – Postmenopausal women and elderly men.

• Thyroidectomy – If presence of large goitre and poor drug compliance.

2. Toxic – nodular goitre

Single adenoma – Plummer’s disease

Multiple adenoma – Multinodular goitre

Usually disease progress from non-toxic to toxic phase

Excess T3, T4

Rx - same as that of Grave’s disease but surgery is preferred.

3. Subacute thyroiditis

Viral infection Enlarged & tender thyroid

Resolve over weeks or months.

If non – tender – called silent thyroiditis

Initially, T4 & T3 are elevated and TSH is low, but as the disease progresses T4 & T3 will drop and TSH will rise

Rx

• In most cases only symptomatic Rx is necessary e.g. acetaminophen 0.5 g four times daily

• If pain, fever, and malaise, a short course of NSAID or a glucocorticoid such as prednisone 20mg three times daily for 7-10 days may be necessary to reduce the inflammation.

• L-thyroxine is indicated during the hypothyroid phase of the illness. 10% of the patients will require L-thyroxine long term.

4. Thyroid storm

Extreme manifestation of thyrotoxicosis

Fatal & occurs in association with Grave’s or Toxic Nodular Goitre.

More common in pts. who are incompletely / not treated for thyrotoxicosis.

Due to cytokine release & acute immunological disturbance.

If pt. not rendered euthyroid before surgery, increased risk.

CF – Fever, sweating, tachycardia, arrhythmias, diarrhoea, delirum, Pul. Edema, stupor, coma & death.

Rx Aim

• To decrease both synthesis & release of thyroid hormones• Block increased adrenergic activity• Supportive measures

Propylthiouracil – 250 µg QID orally

Collosal Iodine (saturated KI solution) > 6 mg daily orally OR Sodium ipodate 1 g orally daily

Propranolol 1 – 2 mg slow IV f/b 40 – 80 mg oral

Hydrocortisone 100 mg IV f/b oral prednisolone

Diltiazem ( if propranolol CI) 60 – 120 mg BD oral

Rehydration, anxiolytics, external cooling & antibiotics.

If above measures fail, Plasmapheresis recommended.

5. Neonatal Hyperthyroidism

Some neonates born to mothers with Graves’ disease will be hyperthyroid at delivery

Antithyroid drug therapy up to 12 weeks

• Propylthiouracil 5–10 mg/kg per day or • Methimazole 0.5–1 mg/kg per day

One drop per day of SSKI (Saturated Solution of Potassium Iodide) in the first few days.

Thyroid Drugs

1. Levo-thyroxine (T4) Sodium

Preferred over Liothyronine (T3)

Sustained & uniform action

Low arrhythmic risk

Easily deiodinated to T3

Good oral BA

Long t ½ - once daily dose.

Sucralfate, iron, Ca+ & PPI reduce absorption (empty stomach).

2. Liothyronine (T3) Sodium

Not freely available

Occasionally used IV along with L-thyroxine in myxoedema coma.

Costly, short t ½ .

Used in short term suppression of TSH in pts. undergoing thyroid cancer surgery & in case of DID deficiency who fail to convert T4 to T3.

Adverse effects

Tachycardia, palpitation, weight loss, diarrhoea, insomnia, heat intolerance.

Rapid correction of hypothyroidism in IHD pts. can precipitate angina.

Drug Interactions

TH therapy increase insulin requirement in diabetic pts.

Pts. on TH therapy need large doses of digoxin.

During concomitant therapy, doses of anticoagulants need to be reduced.

Thyroid Inhibitors

A. Inhibit Thyroid Hormone synthesis (Thioamides)

Propylthiouracil, Methimazole & Carbimazole.

Bind to thyroid peroxidase enzyme & inhibit oxidation, iodination & coupling.

Thyroid colloid depletes & blood levels of T3, T4 fall.

Goitre may occur with treatment.

Methimazole – active metabolite of Carbimazole & 10 times more potent than Propylthiouracil.

Orally absorbed, wide distribution, metabolized/excreted in urine.

Adverse effects

Reversible hypothyroidism & goitre ( TSH ) - overtreatment.

GI intolerance, skin rash, joint pain.

Loss of hair & taste, fever, cholestatic jaundice, lupus like reaction.

Rare important S/E – Agranulocytosis.

Doses

• Propylthiouracil – 50 – 150 mg TDS (MD: 25 – 50 mg TDS)• Methimazole – 5 – 10 mg TDS (MD: 5 – 15 mg OD)• Carbimazole – 5 – 15 mg TDS (MD: 2.5 – 10 mg OD)

Uses

Grave’s disease, Toxic Nodular Goitre (I 131).

Preoperatively – render pts. euthyroid.

Along with I 131 ( to prevent initial hyperthyroidism following I 131due to release of stored T4).

Advantages

No surgical risk, scar or injury.

Reversible hypothyroidism

Used in children / young adults.

Disadvantages

Long Rx / Relapse rate high.

Uncooperative / Unintelligent pt.

Drug toxicity

B. Inhibit Iodide Trapping ( Ionic Inhibitors)

Thiocynates, Perchlorates & Nitrates.

Block N+/ I+ symporter (NIS).

Perchlorates 10 more times potent than thiocynates in blocking NIS.

These drugs not used due to toxicity.

C. Inhibit Hormone Release ( Iodine & Iodides)

Commonly used preps. are Lugol’s Iodine (collosal iodine 0.16 % or aqueous KI solution).

Oldest remedy for thyroid disorder.

Excess iodide if introduced, shows Wolff Chaikoff effect resulting in decreased T3, T4.

Inhibit hormone release ( Thyroid constipation), less vascular.

Effect fades after few days, gland escapes and hormone synthesis resumes.

Uses

Preoperatively – surgery preparation in Grave’s disease. Lugol’s Iodine given 10 days before surgery. Carbimazole added before starting iodide to render euthyroid.

Thyroid storm – L.I. solution (6 – 10 drops) orally lowers hormone release & conversion.

Prophylaxis of Goitre – as iodized salt

As antiseptic – tincture iodine, povidone iodine.

Adverse events

Acute reaction – iodine sensitive pts.

Chronic overdose (Iodism) – Inflammation of mucous membrane, salivation, lacrimation, rhinorrhoea, burning sensation in mouth.

Iodide cause acne flare up.

D. Destroy Thyroid Tissue

Radioactive Iodine I 131, t ½ - 8 days.

I 131 emit X rays & Beta particles (destructive effect).

Large dose – concentrate colloid – destroy cells from inside.

Pyknosis, necrosis & fibrosis takes place.

Taken as sodium salt of I 131 in water orally.

Diagnostic dose: 25 -100 µ curie

Therapeutic dose: 3 – 6 m curie ( Grave’s ds. & TNG)

Advantage

Simple, inexpensive & OPD basis.

No surgical risk, scar, injury.

Once hypothyroidism corrected, cure is permanent.

Disadvantage

Hypothyroidism – supplemental Thyroxine needed.

Latent reponse

Contraindicated during pregnancy.

Not suitable to young pts. (Risk of Hypo)

Rx of choice in cardiac pts.

E. Iodinated Contrast Media

Oral Ipodate, Ipanoic acid, Diatrizoate IV.

Richly iodinated compounds inhibit DID – 1 & 2. Also peripheral conversion inhibited.

Used as adjunctive therapy with Thioamides.

Can develop resistance. Used for short term treatment of severe hyperthyroidism (control T3).