THYROID DISORDERS

& PARATHYROID DISORDERS

PHARMACOTHERAPY 2

•ONANONG WALEEKHACHONLOET

•THANANAN RATTANACHOTPHANIT

ต ำแหนง Thyroid gland & Parathyroid glands

Larynx

Trachea

Superior parathyroid gland

Inferior parathyroid gland

Thyroid hormone function

• Thyroid hormones are critical determinants of brain and somatic

development in infants and of metabolic activity in adults.

• Thyroid hormones also affect the function of virtually every organ

system.

•Major targets of thyroid hormone: skeleton, heart, and

metabolic regulation

• Thyroid hormones must be constantly available to perform these

functions, there are large stores of thyroid hormone in the thyroid

gland to maintain their availability.

Thyroid disorderI. ควำมผดปกตของกำรท ำงำนของตอม thyroid

- Thyrotoxicosis / Hyperthyroidism

- Hypothyroidism

II. ตอมธยรอยด thyroid ท ำงำนปกต แตมขนำดโตขน

- Diffuse euthyroid goiter

- Solitary thyroid nodule

- Multinodular goiter

III. ควำมผดปกตของ thyroid function test โดยทตอม thyroid

ท ำงำนปกต

- Euthyroid hyperthyroxinemia

- Euthyroid sick syndrome

- Euthyroid hypothyroxinemia

IV. ควำมผดปกตของตอมธยรอยดแบบ subclinical- Subclinical hypothyroidism- Subclinical hyperthyroidism

Thyroid gland

• Biggest endocrine gland

สงเคราะห “Thyroid hormone”

- Triiodothyronine (T3)

- Tetraiodothyronine (Thyroxine) (T4)

สงเคราะห “Calcitonin”

• Synthesis and Release is achieved by an intricate

negative feedback mechanism involving gland

and hypothalamic-pituitary axis

• Autoregulation depend on iodine: Wolff-Chaioff

effect

Wolff-Chaioff effect: A reduction in thyroid hormone levels/production caused

by ingestion of a large amount of iodine

• กลไกการปรบตวของตอมไธรอยดขณะทรางกายมระดบ iodine ในเลอดสงโดยเกดการ

ยบยงการสราง thyroid hormone ชวคราว

Iodine & Thyroid hormones synthesis

• iodine ในอาหารถกเปลยนเปน inorganic iodide และถกดดซมในล าไสเลก เพอน าไปใชในการสราง thyroid hormone

ผำน 3 ข นตอนใหญๆ คอ

1. Iodide transport

2. Oxidation ของ iodine

และ organic iodination

3. การสราง iodothyronine

TG= thyroglobulin, a large glycoprotein

synthesized in the thyroid cell

• Thyroxine (T4) and triiodothyronine (T3) are formed within thyroglobulin

• The unique tertiary structure of this glycoprotein (iodinated tyrosine residues

present in TG) are able to bind together to form active thyroid hormones

Thyroid hormones synthesis

คณสมบต Thyroid hormones: • "double" tyrosine with the critical incorporation of 3 or 4 iodine

atoms• lipid soluble

• T4 and T3 are transported in the bloodstream primarily by three proteins

: thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin

(มากกวารอยละ 99 จบกบโปรตน)

• Circulating T3 : 80 % is derived from extrathyroidal conversion of T4 to

T3, 20% from direct thyroidal secretion

• Only the free thyroid hormone is able to diffuse into the cell and

some tissues, such as the brain, by active transport.

การควบคมการสราง thyroid hormone

Pathway I: ควบคมโดย TSH ซงหล ง

จำก anterior pituitary gland

• The secretion of TSH is itself under

negative feedback control by the

circulating level of free thyroid

hormone and positive influence of

hypothalamic thyrotropin-releasing

hormone (TRH).

Pathway II:

• Extrathyroidal deiodination of T4 to T3

is regulated by a variety of factors

including nutrition, nonthyroidal

hormones, ambient temperatures,

drugs, and illness.TRH= thyrotropin releasing hormone

TSH= thyroid stimulating hormone

Hypothalamus & Pituitary

•Thyroid hormone biosynthesis and secretion are maintained within narrow

limits by a regulatory mechanism that is very sensitive to small changes

in circulating hormone concentrations.

TRH= thyrotropin releasing hormone

TSH= thyroid stimulating hormone

Negative feedback

ถารางกายมระดบธยรอยด

ฮอรโมนในกระแสเลอดสงจะกด

การสรางและหลง TSH ท าให

ระดบ TSH ในกระแสเลอดต าลง

ตรงกนขาม

ถารางกายมระดบธยรอยด

ฮอรโมนในกระแสเลอดลดลงจะ

กระตนการสรางและหลง TSH ให

มระดบสงขน

THYROID FUNCTION TEST: Normal value

Current units SI units

Total T4 4.5-12.0 G/dl 58-155 nmol/L

Free T4 0.8-2.7 ng/dl 10.3-34.8 pmol/L

Free T3 0.2-0.5 ng/dl 3.5-7.7 pmol/L

Total T3 80-200 ng/dl 1.2-3.1 nmol/L

T4 index 1.2-3.6 1.2-3.6

TSH 0.35-6.20 U/ml 0.35-6.20 mU/L

Metabolism of thyroid hormones• Primary metabolism of thyroxine is deiodination.

• Deiodination of T4 may occur by monodeiodination of “outer ring”

producing 3,5,3’- triiodothyronine - T3 by 5’-monodeiodinase.

(T3 is 4 times more potent than T4)

• Deiodination of “inner ring” produce 3,3’,5’ – reverse

triiodothyronine – rT3 (inactive) by 5-monodeiodinase.

• In extrathyroidal tissue: T4 change to T3 by using 5-deiodinases in

liver.

Outer ring Inner ring

5’-monodeiodinase. 5-monodeiodinase.

Metabolism of thyroid hormones

•Beta blockers•High dose propylthiouracil•Steroid

•low T3 & high

of rT3

การสราง Thyroid Hormone

T4 (prohormone) T3 (active hormone)

Thiocyanate

Hypochlorite

17

Thyroid Hormone Synthesis and Secretion Inhibitors

• Blocks iodide transport into the thyroid :

– Bromine, Fluorine, Lithium

• Impairs organification and coupling of thyroid hormones:

– Thionamides, Sulfonylureas, Sulfonamide (?), Salicylamide (?),Antipyrine (?)

• Inhibits thyroid hormone secretion:

– Iodide (large doses), Lithium

MEDICATION &THYROID FUNCTION

Drugs affecting the secretion of TSH

• Dopamine: 1 microgram/kg/min

• Glucocorticoids: dexamethasone at least 0.5 mg/day

hydrocortione at least 100 mg/day

• Octreotide: 100 microgram/day

Drugs affecting the secretion of thyroid hormone

• Lithium: interfere synthesis and decrease secretion (occur in long term

treatment ~ 50%)

• Iodine containing medications: iodide, amiodarone, aminoglutethimide

Drugs affecting T4 absorption

• Colestipol, Cholestyramine, Aluminium hydroxide, Ferrous sulfate,

Sucralfate

MEDICATION AND THYROID FUNCTION

Drugs affecting transportation

• Increased TBG concentration: estrogen, tamoxifen, heroin, methadone,

mitotane, fluorouracil

• Decreased TBG concentration: androgen, anabolic steroids, slow release

nicotinic acid, glucocorticoids

• Displacement from protein-binding site: furosemide, fenclofenac,

mefenamic acid, salicylates

Drugs that alter T4 and T3 metabolism

• Increased hepatic metabolism: phenobarbital, rifampin, phenytoin,

carbamazepine

• Decreased 5-deiodinase activity: PTU, amiodarone, beta antagonist,

glucocorticoids

• Cytokines: interferon alfa, interleukin-2

Hyperthyroidism & Hypothyroidism

Thyroid evaluation

Symptoms of thyroid excess or deficiency

History of familial thyroid abnormality

Examination of thyroid for enlargement, consistency,

nodularity

Medication history

Thyroid function test (TSH, T3, T4)

ผปวยสวนใหญมกจะมาดวยภาวะ

• abnormal thyroid hormone levels

• diffuse or nodular thyroid enlargement

MNG=Multinodular goiter

Physical examination

• Weight

• Blood pressure

• Pulse rate & cardiac rhythm

• Thyroid palpation & auscultation

• Neuromuscular examination

• Eye examination

• Dermatologic examination

• Cardiovascular examination

• Lymphatic examination (nodes and spleen)

23

HyperthyroidismHypothyroidism

Physiological system

Hyperthyroidism(thyrotoxicosis)

Hypothyroidism

Skin --

appendages

warm, moist skin; sweating; fine,

thin hair; Plumber's nails;

pretibial dermopathy (Graves'

disease)

pale, cool, puffy skin; brittle hair

and nails

Eyes, face Upper lid retraction (wide stare);

periorbital edema;

exophthalmos, diplopia (Graves'

disease)

Eyelid drooping; periorbital

edema; puffy, nonpitting facies;

large tongue

Cardiovascular decreased peripheral resistance,

increased cardiac output, stroke

volume, heart rate, pulse

pressure; congestive heart

failure (high-output); increased

contractility,. arrhythmogenic;

angina

increased peripheral resistance,

decreased cardiac output, stroke

volume, heart rate, pulse

pressure; congestive heart

failure (low output); bradycardia

(low voltage ECG with prolonged

PR interval, flat T wave);

pericardial effusion

Physiological

systemHyperthyroidism

(thyrotoxicosis)

Hypothyroidism

Respiratory dyspnea; reduced vital capacity hypoventilation (CO2 retention)

pleural effusions

Gastrointestinal increased appetite; increased

bowel movement frequency;

hypoproteinemia

decreased appetite, decreased

bowel movement frequency;

ascites

CNS Nervousness, hyperkinesia,

variable emotional states

lethargy, neuropathy

Musculoskeletal Weakness; fatigue;

hypercalcemia, osteoporosis,

increased deep tendon reflex

muscle fatigue, reduced deep

tendon reflex, increased

alkaline phosphatase, LDH, AST

Physiological system

Hyperthyroidism (thyrotoxicosis)

Hypothyroidism

Renal Increased renal blood flow;

increased GFR; mild polyuria

Decreased renal blood flow;

decreased GFR; reduced water

excretion

Hematopoietic anemia (increased RBC

turnover); increased

erythropoiesis

anemia (decrease production

rate, decreased iron absorption,

decreased folate acid

absorption, autoimmune

pernicious anemia),decreased

erythropoiesis

Reproductive decreased fertility; menstrual

irregularity; enhanced gonadal

steroid metabolism

infertility;hypermenorrhea,

decreased libido; impotence,

decreased gonadal steroid

metabolism

Physiological system

Hyperthyroidism (thyrotoxicosis)

Hypothyroidism

Metabolic increased basal rate; negative

nitrogen balance,

hyperglycemia; increased free

fatty acids, decreased

cholesterol and triglycerides;

increased hormone

degradation; increased

requirement for fat-and water-

soluble vitamins; enhanced

drug detoxification

decreased basal rate; delayed

insulin degradation, with

increased sensitivity; enhanced

cholesterol and triglyceride

levels; decreased hormone

degradation; decreased

requirements for fat-and

water-soluble vitamins;

decreased drug detoxification.

Thyroid function test

• TSH: the most cost effective

screening test but it is not reliable in

secondary hypothyroidism

• FT4: patients recently treated for

thyroid disorder

• Nonspecific indice: cholesterol and

other lipid profile, SGOT, SGPT, CPK,

Cr

The most common

Lab used:

• TSH,

• total T4

• free T4

• total T3

• free T3

*** Drug or disease state can alter laboratory value

THYROID FUNCTION TEST: Normal value

Current units SI units

Total T4 4.5-12.0 G/dl 58-155 nmol/L

Free T4 0.8-2.7 ng/dl 10.3-34.8 pmol/L

Free T3 0.2-0.5 ng/dl 3.5-7.7 pmol/L

Total T3 80-200 ng/dl 1.2-3.1 nmol/L

T4 index 1.2-3.6 1.2-3.6

TSH 0.35-6.20 U/ml 0.35-6.20 mU/L

CASE 1: 55 yrs Thai female, TSH = 52 U/ml, Free T3 = 0.01 ng/dl

CASE 2: 36 yrs Thai female, TSH = 0.20 U/ml, Free T3 = 0.3 ng/dl

Thyroid binding globulin (TBG) level & Thyroid hormone level

• ความผดปกตของระดบ TBG ในเลอด หรอมปจจยรบกวนการจบกนของธย

รอยดฮอรโมนกบโปรตน จะสงผลใหการวดระดบธยรอยดฮอรโมนรวม (total

T3, total T4) ผดปกตได โดยทระดบ free T3, Free T4 ไมเปลยนแปลงตาม

– รางกายมระดบ IBPs ในเลอดสงขน จะท าให total T3 และ total T4 สง

กวาปกต แต free T3, T4 ปกต เรยกวา Euthyroid hyperthyroxinemia

– รางกายมระดบ IBPs ในเลอดต ำลง จะท าให total T3, total T4 ต ากวา

ปกตแต free T3, T4) ปกต เรยกวา Euthyroid hypothyroxinemia

• มความจ าเปนทตองทราบและประเมนรวมดวยวาผปวยมภาวะใดหรอไมทจะท า

ใหมความผดปกตของโปรตนทจบอยกบธยรอยดฮอรโมน

IBP= iodothyronine binding proteins

ภำวะทท ำใหระดบซร ม TBG ผดปกต

TBG เพมข น TBG ลดลง

ตงครรภ มการเจบปวย (major systemic illness)

ทารกหลงคลอด กลมอาการเนโฟรตค

มภาวะเอสโตรเจนมากเกน ภาวะทพโภชนาการ

ไดรบเอสโตรเจน active acromegaly

ไดรบยาคมก าเนด ไดรบฮอรโมนเพศชาย

ไดรบเฮโรอนไดรบยา tamoxifen ไดรบยากลโคคอรตคอยดในขนาดสง

ไดรบยา perphenazine ไดรบยา L-asparaginase

ตดเชอโรคเอดส พนธกรรม

Chronic active hepatitis

Biliary cirrhosis

Acute intermittent porphyria

พนธกรรม

TBG= thyroid binding globulin

Hyperthyroidism & Thyrotoxicosis

• Thyrotoxicosis (ภาวะธยรอยดฮอรโมนเปนพษ): ภาวะทรางกายม

อาการและอาการแสดงเนองจากเมตะบอลสมของรางกายทสงขน อน

เปนผลมาจากการทระดบธยรอยดฮอรโมนในกระแสเลอดสงกวาปกต

ระดบธยรอยดฮอรโมนทสงขนเกดไดจากหลายสาเหต โดยระดบฮอรโมน

ทสงอาจมการสรางจากอวยวะอนๆ เชน เนองอกของรงไข, ไดรบยาธยรอยด

ฮอรโมนขนาดมากเกนไป หรอ ภาวะธยรอดอกเสบ (Thyroiditis ) ซงมการปลอยธย

รอยดฮอรโมนมากผดปกต

• Tissues are exposed to excessive levels of T4, T3, or both.

• Hyperthyroidism (ภาวะฮยเปอรธยรอยดสซม): ภาวะทตอมธยรอยดท างานมากผดปกตเปนผลใหมการสรางและหลงธยรอยดฮอรโมน

มากกวาปกต

ระดบธยรอยดฮอรโมนในกระแสเลอดทสงขนจะเกดจากความผดปกตจาก

ตอมธยรอยดเอง

Thyorotoxicosis ทม

Hyperthyroidism

•Graves' disease

•Toxic multinodular goiter

•Toxic adenoma

•Hashimoto’s thyroiditis

(Hashitoxicosis )

•Jod-Basedow (Iodine induced)

•TSH- producing pituitary tumor

•Hydratidiform mole

Thyorotoxicosis ทไมม

Hyperthyroidism

•Subacute thyroiditis

•Transient painless thyroiditis

(Postpartum thyroiditis )

•Lymphocyte (silent) thyroiditis

•Thyrotoxic factitia

•Ectopic thyroid: Struma ovarii

Metastatic follicular carcinoma

•Drug associated thyroiditis

(amiodarone, lithium )

•Cytokine associated thyroiditis

(Interferon, Interleukin-2 )

HYPERTHYROIDISM

Most common causes:

• Graves’ disease: an autoimmune disorder in which thyrotropin

receptor antibodies (TRAbs) stimulate the TSH receptor,

increasing thyroid hormone production. (60-90%)

• Toxic multinodular goiters (TMNG, 10-20%)

• Toxic adenoma: autonomous hormone production can be

caused by somatic activating mutations of genes regulating

thyroid hormone synthesis (5-10%)

Epidemiology

• Women > Men (2% : 0.2%) (~ 10 times)

• Peak incidence in children: 10-12 year old

CASE FINDING FOR THYROID DYSFUNCTION

• Previous thyroid dysfunction

• Goiter

• Surgery or radiotherapy affecting the thyroid gland

• DM

• Vitiligo (depigmentation of parts of the skin)

• Pernicious anemia

• Premature gray hair

• Medications: lithium, amiodarone, radiocontrast, potassium

iodide

Goiter: a swelling of the neck or larynx resulting from enlargement of the

thyroid gland (thyromegaly), associated with a thyroid gland that is not

functioning properly.

Signs & Symptoms of Hyperthyroidism

• ผปวยบางรายอาจไมมอาการหรอ

อาการแสดงทเปนลกษณะจ าเพาะ

ของภาวะธยรอยดฮอรโมนเปนพษ

โดยเฉพาะในผปวยสงอาย

• บางรายอาจมอาการและอาการแสดง

ทางระบบใดระบบหนง

• บางรายมอาการตรงกนขามกบอาการ

และอาการแสดงทควรจะเปน

COMPLICATIONS

• Atrial fibrillation

• CHF

• Osteoporosis

Laboratory test: Hyperthyroidism• Hormone:

– Low TSH, Elevated free and total T3 and T4 serum concentrations,

particularly in more severe disease.

• 90%: T4 และ T3 สงขน

• 5-30%: T3 สง แต T4 ปกต (T3 toxicosis)

• พบนอยมาก: T4 สง แต T3 ปกต (T4 toxicosis)

• Radioactive iodine uptake (RAIU): การตรวจความสามารถใน

กระบวนการจบสารไอโอดนของตอมธยรอยด บงชสภำวะกำรท ำงำนของ

ตอมธยรอยด

–Normal 24-hour RAIU ranges from 10% to 30%

–Elevated RAIU by the thyroid gland when hormone is being overproduced;

–Suppressed RAIU in thyrotoxicosis due to thyroid inflammation (thyroiditis)

39

Laboratory test: Hyperthyroidism

• วธทดสอบ: ใหผปวยกน Radioactive iodine (ขนาดโดยทวไปประมาณ

5-20 uCi) แลววดปรมาณ Radioactivity ทตอมธยรอยดตามเวลาท

ก าหนดไวหลงกน Radioactive iodine และค านวณเปนคารอยละของ

จ านวน Radioactivity ทไดรบ

• ไมแนะน า ใหท าการตรวจ RAIU ในผปวยทมอาการชดเจนทกราย

• ขอหามส าหรบการตรวจ RAIU ไดแก ภาวะตงครรภ, ขณะใหนมบตร, และผทแพ

สารไอโอดน

• 131-ไอโอดน (I 131) half-life 8 days, 123-ไอโอดน I 123 half- life 13 hours

Differential diagnosis of thyrotoxicosis

hCG= human chorionic gonadotropin; RAIU = radioactive iodine uptake;

TSAb = thyroid-stimulating antibody; TSH = thyroid-stimulating hormone.

a = The RAIU may be decreased if the patient has been recently exposed to excess

iodine.

• Other tests:

– Thyroid-stimulating antibodies (TSAbs)

– Thyroglobulin (TG)

– Thyrotropin receptor antibodies

41

Laboratory test: Hyperthyroidism

HYPERTHYROIDISM (THYROTOXICOSIS)

Treatment goals :

Reverse sign & symptoms of hyperthyroidism, reduce goiter

size,

Normalize thyroid hormone levels,

Prevent thyroid storm,

Improve cardiac function and prevent systemic embolism

Preserve bone density and prevent osteoporosis

Improve overall functional capacity and quality of life

Graves’ disease

• พบไดบอยในชวงอาย 20-50 ป

• ลกษณะทางคลนก: hyperthyrodism, diffuse

goiter, ophthalmopathy, dermopathy “localized

myxedema”

• Autoimmune disease: สามารถตรวจ Autoantibody ตอ Ag หลายชนดท

Thyroid cells ไดแก TSH receptor (TSHR), thyroid peroxidase

(TPO), thyroglobulin (TG) และ thyroidal iodide transporter

• 80-100% ของผปวย ม Ab ชนด IgG ตอ TSHR (TSHRAb)

• TSHRAb ชนดทพบบอยและมปรมาณมากทสด ไดแก Thyroid

Stimulating Immunoglobulin (TSI) หรอ Thyroid Stimualting

Antibody (TSAb)

การรกษา Hyperthyroid ทเกดจากโรค Graves' disease

ม 3 วธ

1. การรกษาดวยสารรงส (Radioactive iodine: I131)

2. Subtotal thyroidectomy

3. Medical treatment

The American Association of Clinical Endocrinologists Guideline (AACE)

Factors need to be considered

• Cause of hyperthyroidism

• Severity

• Patient’s age

• Size of goiter

• Other complications

• Social and economic issues

Method Cost Efficacy Failure Adverse events

Surgery

Thyroidectomy

total or near

total

5,000-

20,000

70-80%

Graves’disease

Toxic adenoma

Toxic multinodular

goiter

20-30% Hypothyroid 20-30%

vocal abnormal 1:500

Hypoparathyroid

1:500

RAI 1,800-

3,000

70-80%

Graves’disease

Toxic multinodular

goiter

Toxic adenoma

no data Hypothyroid 3-6%

Teratogenicity

Medications ?? 30-40%

Graves’disease

60% 5-10% Hypothyroid

S/E, hypersensitivity

Surgery 131I Antithyroid drugs

Substantial comorbidity

- Cardiopulmonary diseases

- End stage cancer

Pregnancy (trimester 1 and 3)

• Pregnancy

• Lactation

• Thyroid cancer

• Unable to comply with

guideline

• Females planing a

pregnancy with in 4-6

mon

Major adverse

reactions

Contraindications of each treatment

https://www.aace.com/publications/guidelines

: update May 24, 2011

การรกษา Hyperthyroid ทเกดจากโรค Graves' disease

Advantages Disadvantages Comment

Rapid, effective

treatment,

especially in patients

with large goiters

•Most invasive

•Least costly in long

term after quality-

of-life adjustment

•Permanent

hypothyroidism

•Pain, scar

•Potential choice in

pregnancy if major side

effect from antithyroid

drugs

•Potential complications

(recurrent laryngeal

nerve damage,

hypoparathyroidism)

•Useful when coexisting

suspicious nodule

present

•Option for patients who

refuse radioiodine

Surgery

SURGERY

• Treatment of choice for extremely large nodule (>80g),

severe ophthalmopathy, not response to antithyroid

medications

• Complication: rate < 4 %

- Recurrent hyperthyroidism

- Hypothyroidism

- Hypoparathyroidism

- Vocal cord abnormalities

SURGERY

• Prepartion of surgery:

- PTU or MMI for 6-8 weeks until euthyroid (having normal thyroid

gland function)

- Iodide 500 mg/day for 10-14 days

- Propranolol for 10-14 days

• Relapse of hyperthyroidism occurs in at least 10%

• Permanent hypothyroidism occurs in 5% of patients within the

first year, and thereafter in one or two patients per year.

การรกษา Hyperthyroid ทเกดจากโรค Graves' disease

Advantages Disadvantages Comment

• Cure of

hyperthyroidism

• Lowest cost,

before adjustment

for quality of life

• Permanent hypothyroidism

almost inevitable

• Might worsen

ophthalmopathy

• Pregnancy must be

deferred for 6–12 months;

no breastfeeding

• Small potential risk of

exacerbation of

hyperthyroidism

• Best treatment for

toxic nodules and

toxic multinodular

goiter

Radioactive iodine (131I)

RADIOACTIVE IODINE (RAI)

• 131I colorless and tasteless liquid that is well absorbed and

concentrates in the thyroid

• Mechanism: 131I disrupt hormone synthesis

• Benefit for debilitated, cardiac, elderly, drug failure or toxic,

relapse after surgery

• Β-blockers are adjunct therapy prior to RAI. 1/+00

• If MMI is given, discontinue MMI 3-5 days before RAI, restart

3-7 days later and taper over 4-6 weeks.

• If hyperthyroidism persists after 6 month of RAIs, retreatment with RAI is suggested. 2/+00

FACTS ABOUT RADIOACTIVE IODINE

• Pregnancy is an absolute contraindication

– After receiving RAI for 4-6 months,

• patient should avoid pregnant.

• It needs 3-4 months in men to allow for turnover of

sperm production.

• Radiation thyroiditis can occur within the first two weeks after

RAI

• Hypothyroidism commonly occur following RAI

– Hypothyroidism after RAI for 6 months may be transient or

permanent

• RAI worsening ophthalmopathy

• Theoretical risk of genetic abnormality: 0.005%

Instructions for patients after RAI

• Do not share food or eating utensil for 5 days

• Avoid close contact with infants, young children (under 8 years),

pregnant women for 5 days

• No breast feeding is allowed for lactation: at least 6 weeks

• Flush the toilet twice after urinating and wash hand throughly

• If note increased nervousness, tremulousness, or palpitations,

call a physician

การรกษา Hyperthyroid ทเกดจากโรค Graves' disease

Advantages Disadvantages Comment

•Noninvasive

•Low initial cost

•Low risk of permanent

hypothyroidism

•Possible remissions due

to immune effects

•Low cure rate (30–

80%; average 40–

50%)

•Adverse drug

reactions

•Drug compliance

•First-line treatment in

children, adolescents,

and pregnancy

•Initial treatment in

severe cases or

preoperative

preparation

Methimazole (PTU only second-line therapy)

บญชยาหลกแหงชาต

carbimazole, a precursor of MMI, 10 mg of carbimazole is metabolized to approximately 6 mg of MMI

THIOUREA DRUGS (Thioamides)

• Mechanism : Methimazole (MMI), Propylthiouracil (PTU)

– inhibit the peroxidase enzyme system (peroxidation) and coupling process

– PTU can also inhibit peripheral conversion from T4 to T3

• Patient characteristics for good outcome : small goiter (<50g), short duration of

disease (< 6 month), no previous history of relapse with antithyroid drugs

Pharmacology Thiourea drugs (Thioamides)

Serum protein binding ~75% noneSerum half-life 75 นาท ~4-6 ชวโมง

Volume of distribution ~20 ลตร ~40 ลตร

Metabolism of drug illnessSevere liver disease ปกต ลดลง

Severe kidney disease ปกต ปกต

PTU MMI

tab 50 mg tab 5, 10, 20 mg

Transplacental passage นอย มากกวา

Levels in breast milk นอย มากกวา

Potency 1 10Inhibition of peripheral ม ไมม

conversion of T4 to T3

All adverse reactions 7.1% 3.3%

Major adverse reactionsAgranulocytosis 0.4% (idiosyncrasy) 0.1%(dose related)

Hepatotoxicity hepatocellular damage cholestasisVasculitis พบบอยกวา พบนอยกวา

PTU MMI

Adverse effectCross sensitivity: 50%

Most common

• Rash

• Itching

• Hives (urticaria)

• Abnormal hair loss

• Skin Pigmentation

• Transient leukopenia

(WBC < 4000/mm3)

Less common

• Swelling

•Nausea

•Vomiting

•Heartburn

•Loss of taste

•Joint or muscle aches

•Numbness and headache

Adverse effect

Rare case but severe (first 2 month of therapy)

• Agranulocytosis: PTU> MMI

• Aplastic anemia

• Lupus-like syndrome: occur after 6 months

• Polymyositis

• Hepatotoxic: occur within the first 3 months

• Hypoprothrombinemia

• Vasculitis

** If these complications occur, antithyroid drugs should

be discontinued (absolute contraindication)

Agranulocytosis: Thiourea drugs

One of serious adverse effects of thiourea drug therapy

An idiosyncratic reaction: mostly occur in the first 3 month

Common among patients over 40 year old

Rare among patients receiving < 30 mg of MMI/day

Symptoms: fever, rash, jaundice, arthralgia, oropharyngitis

Granulocyte count <250 per cubic millimeter

Patients can recover within 2-3 wks after the drug is stopped.

Warning: Agranulocytosis is an absolute contraindication

of antithyroid–drug therapy.

THIOUREA DRUGS

•MMI should be used in virtually every patient who chooses

antithyroid drug therapy for Grave disease,

– except during the first trimester of pregnancy when PTU is

preferred, in the treatment of thyroid storm.1/++0

•Patient should be alerted to stop the medications (PTU and MMI)

immediately and call their physician

• when there are symptoms suggestive of agranulocytosis or

hepatic injury. 1/+00

•Medication should be continued for approximately 12–18 months,

– then tapered or discontinued if the TSH is normal at that time.

1/+++

THIOUREA DRUGS

•If a patient with Grave’s disease becomes hyperthyroid after

completing a course of MMI,

• consideration should be given to treatment with RAI or

thyroidectomy.

• Low-dose MMI treatment for longer than 12–18 months may

be considered in patients not in remission who prefer this

approach. 2/+00

•When MMI is discontinued,

• thyroid function testing should continue to be monitored at 1–

3-month intervals for 6–12 months to diagnose relapse early.

Thiourea drugs

• Usual initial dose

– MMI 10-20 mg OD (single dose), Max dose 120 mg/day

– PTU 100 mg TID (300-600 mg/day), Max dose 1200 mg/day

• Improvement in symptom & lab test should be ensured within 4-8 wks

• Monthly dose titrations as needed (based on symptoms and free T4

concentrations); TSH may remain low months after starting therapy

• Maintenance dose for 12-18 month

– MMI : once euthyroid, may reduce to 5–10 mg/day

– PTU: once euthyroid, may reduce to 50 mg 2-3 times daily

Monitoring: baseline, 2 month, 6 month, course of therapy

• After remission: monitoring every 6-12 month

THIOUREA DRUGS IN PREGNANCY

• PTU should be used when antithyroid drug therapy

is started during the first trimester.

• MMI should be used when antithyroid drug therapy

is started after the first trimester. 1/+00

• Patients taking MMI who decide to become pregnant should be

switched to PTU as soon as possible in the first trimester and

changed back to MMI at the beginning of the second trimester.

2/+00

• GD during pregnancy should be treated with the lowest possible

dose of antithyroid drugs.1/+00

BETA BLOCKER

• CCBs: verapamil and diltizem oral can be used in patients with

contraindications with beta-adrenergic blockade

•Beta-adrenergic blockade should be given to elderly patients with

symptomatic thyrotoxicosis and to other thyrotoxic patients with

resting heart rates in excess of 90 bpm or coexistent cardiovascular

disease. 1/++0

•Beta-adrenergic blockade should be considered in all patients with

symptomatic thyrotoxicosis. 1/+00

•Contraindications of beta-adrenergic blockade: severe asthma,

CHF, cardiomyopathy

• used as adjunctive therapy with antithyroid drugs, RAI, or iodides when

treating Graves’ disease or toxic nodules; in preparation for surgery; or in

thyroid storm.

• used to ameliorate thyrotoxic symptoms such as palpitations, anxiety, tremor,

and heat intolerance,

BETA BLOCKER

From AACE guideline 2011

IODIDES

• Short term therapy before surgical, after radiotherapy, acutely thyroid

storm

– Often used as adjunctive therapy to surgery patient to shrink the

size of the gland.

– Do not use in the days before ablative surgery because it may

reduce uptake of radioactive iodine

• Mechanism: block releasing and inhibit synthesis of thyroid hormone.

• Limited efficacy after 7–14 days of therapy because thyroid hormone

release will resume.

• Symptom improvement occur 2-7 day after treated.

ADR : Hypersensitivity (rash, fever, rhinitis,cough)

Salivary gland swelling

Iodism (Metalic taste, burning mouth, stomach upset)

Gynecomastia

IDODIDES

• Lugol solution: 0.1-0.3 ml three time daily

(5% iodine +10% potassium iodide)

(6.3–8 mg of iodide per drop)

20 drop = 1 ml, 1 drop =0.05 ml

Potassium iodide: 60 mg three time daily

130-mg tablets contain 100 mg of iodide

Saturated solution of potassium iodide,

SSKI (38–50 mg of iodide per drop)

typical starting dose of SSKI is 3 to 10 drops daily (120

to 400 mg) in water or juice.

SUBCLINICAL HYPERTHYROIDISM

• Serum TSH below the lower limit of the reference range combined

with free T4 and T3 concentrations that are normal

• Potentially increase risk to develop cardiac and bone density

abnormality

• Few data are available to guide clinical decision regarding the

treatment of subclinical hyperthyroidism

• These patients could be treated with antithyroid agents, surgery,

radioactive iodine.

From AACE guideline 2011

Most practitioners agree that treatment of older patients (> 65 yrs)

with TSH values below 0.1 milli–international unit/L is reasonable.

SUBCLINICAL HYPERTHYROIDISM

THYROID STORM

Precipitating factor

- Surgical procedures

- RAI treatment

- Infection

- Noncompliance of thioamides

- Illness

- Accident

- Excessive iodine

- Excessive thyroid hormone

Signs and symptoms

- High Fever

- Tachycardia

- Agitation

- Weakness

- Dehydration

- Delirium

- Coma

- Nausea/vomiting

- Diarrhea

A life-threatening medical emergency

Diagnosis of thyroid storm

From AACE guideline 2011

Thyroid storm : Treatment1. Correction for hyperthyroidism: suppression of thyroid hormone,

formation and secretion

- Antithyroid drugs: PTU high dose (1200-1500 mg divide to 4-6

times/day)

- Lugol’s solution

- Dexamethasone (inhibit conversion T4 to T3)

- Antiadrenergic therapy

- Other methods: plasmapheresis to remove excess hormone (and to remove

thyroid-stimulating immunoglobulins in Graves’ disease) when the patient has not

responded to more conservative measures, although these measures do not always

work

Inhibition of thyroid hormone biosynthesis: PTU, MMI

Inhibition release of thyroid hormone from the

thyroid gland:

potassium iodide, lithium,

ipodate

Decreasing of the peripheral effects of thyroid

hormone:

PTU, corticosteroids,

ipodate, iopanic acid

Drugs used in thyroid storm

Drug Regimen

Propylthiouracil 900–1,200 mg/day orally in four or six divided doses

Methimazole 90–120 mg/day orally in four or six divided doses

Sodium iodide Up to 2 g/day IV in single or divided doses

Lugol’s solution 5–10 drops three times a day in water or juice

Saturated solution of

potassium iodide

1–2 drops three times a day in water or juice

Propranolol 40–80 mg every 6 hours

Dexamethasone 5–20 mg/day orally or IV in divided doses

Prednisone 25–100 mg/day orally in divided doses

Methylprednisolone 20–80 mg/day IV in divided doses

Hydrocortisone 100–400 mg/day IV in divided doses

• PTU in large doses may be the preferred thionamide because, in

addition to interfering with the production of thyroid hormones, it also

blocks the peripheral conversion of T4 to T3. However, β-blockers

and corticosteroids will serve the same purpose.

77

Drugs used in thyroid storm

• Iodides, which rapidly block the release of preformed thyroid

hormone, should be administered after thionamide is initiated to

inhibit iodide utilization by the overactive gland.

– If iodide is administered first, it could theoretically provide

substrate to produce even higher levels of thyroid hormone.

• Corticosteroids are generally recommended, although there is no

convincing evidence of adrenocortical insufficiency in thyroid storm,

and the benefits derived from steroids may be caused by their

antipyretic action and their effect of stabilizing blood pressure.

Thyroid storm : Treatment

2. Prevention and correction for complications

- Water and electrolyte imbalance: D5W

- Fever : paracetamol (do not use aspirin or other nonsteroidal

antiinflammatory agents because they may displace bound thyroid

hormone)

- CHF, arrhythmia

3. Correction for precipitating factors

Thyroiditis (Inflammatory Thyroid Disease)

• It should be suspected if patient have

pain and tenderness in the thyroid

region

• Hyperthyroidism from thyroiditis usually

is mild and lasted only a few weeks

• Treatment with antithyroid or RAI is not

work.

• Short term salicylate or glucocorticoid

may be needed to relieve thyroid pain

and tenderness

Thyroiditis: hyperthyroidism results from unregulated, inflammation-

induced release of stored thyroxine and triiodothyronine.

Treatment consideration for specific population

• Pregnancy: use PTU low dose ( 300 mg or less and

tapered to 50 to 150 mg daily after 4 to 6 weeks)

• Neonatal and pediatric: PTU 5 -10 mg/kg/day or MMI 0.5-1

mg/kg/day for 8-12 weeks, Iodides for few days

HYPOTHYROIDISM (ภาวะพรองธยรอยดฮอรโมน)

• Women > men (1.4% : 0.1%)

• Majority of patients have

primary hypothyroidism due to

thyroid gland failure due to

chronic autoimmune thyroiditis.

• Cretinism (Child)

• Myxedema (Adult)

• Hashimoto’s thyroiditis

Special populations with higher risk:

• Postpartum women,

• FH of autoimmune thyroid disorders,

• Patients with previous head and neck or

thyroid irradiation or surgery,

• Other autoimmune endocrine conditions

(e.g., Type 1 DM, adrenal insufficiency,

and ovarian failure),

• Some other non-endocrine autoimmune

disorders (e.g., Celiac disease, vitiligo,

pernicious anemia, sjögren’s syndrome,

and multiple sclerosis),

• Primary pulmonary hypertension,

• Down’s and turner’s syndrome

Causes of Hypothyroidism

Primary hypothyroidism

• Hashimoto’s disease

• Iatrogenic hypothyroidism

• Iodine deficiency

• Enzyme defects

• Thyroid hypoplasia

• Goitrogens

82

Caused by drug induce: amiodarone,

povidone iodine, iodinate contrast

media, lithium, nitroprusside

Secondary hypothyroidism

• Pituitary disease

• Hypothalamic disease

Goitrogens = substances that suppress the function of the thyroid gland

by interfering with iodine uptake, which can, as a result, cause an

enlargement of the thyroid

Causes of Hypothyroidism

1.1) Loss of functional thyroid tissue

• Postoperative and postradiation (I131 or external irradiation)

• Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis)

• Reversible autoimmune hypothyroidism (Silent and postpartum

thyroiditis, cytokine thyroiditis)

• Idiopathic myxedema

1. Primary (Thyroidal hypothyroidism)

1.2) Functional defects in thyroid hormone biosynthesis and

releases

• Congenital defects in thyroid hormone biosynthesis

• Iodine deficiency

• Iodine – induced hypothyroidism

• Drug : antithyroid agents, lithium, natural and synthetic goitrogenic

chemicals

2.1) Loss of functional tissue

• Tumors ( pituitary adenoma, craniopharyngioma, meningioma, dysgerminoma, glioma, metastasis )

• Trauma ( Surgery, irradiation, head injury )

• Vascular ( ischemic necrosis, hemorrhage, stalk interruption, aneurysm of internal carotid a. )

• Infections ( abscess; tuberculosis, syphilis, toxoplasmosis )

• Infiltrative ( sarcoidosis, histiocytosis, hemochromocy tosis )

• Chronic lymphocytic hypophysitis

• Congenital ( pituitary hypoplasia, septo-optic dysplasia, basal encephalocele )

2. Central (hypothalamic/pituitary) hypothyroidism

2.2) Functional defects in TSH biosynthesis and release

• Isolate TSH deficiency, TSH synthesis defect, defect in TSH receptor

• Mutation in genes encoding for TRH receptor, TSH- or Pit-1

• Drugs : dopamine, glucocorticoids, L-thyroxine withdrawal

3. Peripheral (extrathyroid) hypo thyroidism

Thyroid hormone resistance

Sign & SymptomGeneral: Cold intolerance, weight gain,

decrease appetite and sweating,easily

fatigue

Head: Dry, brittle, sparse hair

Face: puffy face, large tongue

Neck: goiter in primary hypothyroidism

Cardiac: Cardiac enlargement, poor heart

sounds, dypsnea, low output failure

GI: Constipation

Genitourinary: Amenorrhea

Extremities: Broad hand and feet, cold

and dry skin, brittle nail, yellowish skin

Neuromuscular: Muscle pain and

weakness, paresthesia, delay deep tendon

reflexes

Emotional: Emotional instability,

depression, lethargy, decrease energy,

increase sleep requirement

Thyroid Function Test

• In 1๐ hypothyroidism, TSH level should be elevated.

• In 2๐ hypothyroidism, TSH levels may be within or below the reference range;

when TSH bioactivity is altered, the levels reported by immunoassay may

even be elevated.

• Free and/or total T4 and T3 serum concentrations should be low.

86

TREATMENT: HYPOTHYROIDISM

TREATMENT GOALS :

• Reverse physical finding , and normalize thyroid hormone level

• Reduce goiter size

• Reduce serum cholesterol level

• Improve quality of life

• In neonate and children : maintain normal growth, physical and

mental development

• There is general agreement that patients with primary hypothyroidism

with TSH levels above 10 mIU/L should be treated, which patients with

TSH levels of 4.5-10 mIU/L will benefit is less certain.

Complications:

• CNS: depression, dementia, psychosis, convulsion

• Neuromuscular: Malaise, increasing of creatine

phosphokinase (CPK)

• CVS: increasing risk of coronary heart disease

TREATMENT

Drug of Choice : Sodium levothyroxine (L-thyroxine)

• Daily dosage of L-thyroxine is dependent on age, sex, body size (need

Ideal body weight for daily requirement)

• Initial dose:

• Existing cardiovascular disease 12.5-25 microgram/day

• Adult: 75-200 microgram/day or 1.7 microgram/kg/day

• Children: 4 microgram/kg/day

• Elderly: < 1microgram/kg/day

• Dose titration based on response (control of symptoms, normalization of

TSH and free T4), Can increase or decrease in 12.5- to 25-mcg/day

increments

Adverse effect: hyperthyroidism, osteoporosis, drug allergy, adrenal

crisis.

Monitoring

Plasma TSH concentrations begin to fall within hours and are

usually normalized within 2 weeks,

but they may take up to 6 weeks for some patients, depending

on the baseline value.

TSH concentration is the most sensitive and specific monitoring

parameter for adjustment of L-thyroxine dose. 90

Therapeutic Monitoring

• Patients should be evaluated q 6-8 weeks initially.

• TSH and T4 concentration should be checked monthly until

euthyroid state is achieved.

• Once TSH is normal: visit q 6-12 months is sufficient, TSH should

be measured at least annually.

Drug/Dosage Form Content Relative Dose Comments/Equivalency

Levothyroxine

Synthroid, Levothroid, Levoxyl,

Thyro-Tabs, Unithroid, and other

generics 25, 50, 75, 88, 100, 112,

125, 137, 150, 175, 200, 300 mcg

tablets; 200 and 500 mcg per vial

injection

Synthetic

T4

100 mcg Stable; predictable potency; generics

may be bioequivalent; when switching

from natural thyroid to L-thyroxine,

lower dose by one half grain; variable

absorption between products; half-life

= 7 days, so daily dosing; considered

to be drug of choice

Thyroid USP

Armour Thyroid, Nature-Throid, and

Westhroid (T4:T3 ratio approximately

4.2:1);

Armour, one grain = 60 mg; Nature-

Throid and

Westhroid, one grain = 65 mg. Doses

include 1/4, 1/2, 1, 2, 3, 4, and 5 grain

tablets

Desiccate

d

pork

thyroid

gland

1 grain

(equivalent

to 74 mcg

[˜60–100]

mcg of T4)

High T3:T4 ratio; inexpensive

Liothyronine

Cytomel 5, 25, and 50 mcg tablets

Synthetic

T3

33 mcg

(˜equivalent

to 100 mcg

T4)

Uniform absorption, rapid onset; half-

life = 1.5 days, rapid

peak and troughs

Liotrix

Thyrolar 1/4-, 1/2-, 1-, 2-, and 3-

strength tablets

Synthetic

T4:T3 in

4:1 ratio

Thyrolar 1

= 50 mcg

T4 and 12.5

mcg T3

Stable; predictable; expensive; lacks

therapeutic rationale

because T4 is converted to T3

peripherally. 91

92

Dosage adjustments: L-thyroxine

• Bioequivalent

–If dosage, type, or brand of thyroid preparation changed, TSH

concentration should be measured after 8-12 weeks.

• Decreases in L-thyroxine requirements occur as patients age and following

significant weight loss.

• Patients older than 50-60 years,

– without evidence of coronary heart disease (CHD) may be started on

doses of 50 μg daily.

– with known CHD, usual starting dose is reduced to 12.5-25 μg/day.

• In pregnancy thyroid hormone requirements are increased, then revert

back to baseline after delivery

• Sodium levothyroxine has narrow therapeutic range

• Excessive dose of thyroid hormone may lead to CHF, angina pectorisand MI

ขอมลยา L-thyroxine

• Drug interactions:

- Decrease absorption: cholestyramine, ferrous sulfate, calcium,

antacid, sucralfate, lovastatin

- Protein binding: anticonvulsants

- Increase metabolism: rifampin, phenytoin, carbamazepine,

phenobarbital

L-thyroxine is better absorbed before a meal, instructing patients to

consistently take it with water between 30 and 60 minutes prior to

eating breakfast or at bedtime 4 hours after last meal;

• L-thyroxine should be protected from light and moisture.

Effects of hypothyroidism on some drugs

• Digitalis (increased sensitivity to the digitalis effect)

• Insulin (Insulin degradation may be delayed)

• Warfarin (delays the catabolism of clotting factors)

• Barbiturate, Phenothiazines, Opioid analgesics (increased

sensitivity may increase carbon dioxide retention and precipitate

myxedema coma)

•Metabolism of drugs can be altered for patients with hypothyroidism.

Drug induced thyroid disorders

Drug Mechanism Results

Nitroprusside inhibit hormone effect hypothyroidism

Lithium inhibit hormone release hypothyroidism

Iodides Wolff-Chaikoff effect hypothyroidism or

or iodine-containg hyperthyroidism

Sertraline increase T4 elimination hypothyroidism

Sulfonylureas, inhibit organic bindiing hypothyroidism

sulfonamides

Immunotherapy Autoimmune process hypothyroidism or

hyperthyroidism

Effect of Thyroid Status on Drug Action

Drug Hyperthyroidism Hypothyroidism

Sympathomimetics increase response Blunted response

Digoxin increase Vd, clearance increase sensitivity

Insulin increase metabolism, Prolong effect

increase clearance

Coumadin decrease need of drugs increase need of drugs

Beta-blocker increase clearance not significant

Theophylline not significant decrease clearance

Cortisol decrease half life increase half life

SUBCLINICAL HYPOTHYROIDISM

• Normal free T4 but elevated TSH

• Therapy is recommended if thyroid autoantibodies are

positive: levothyroxine

• If not treated, the patient should be evaluated at yearly

intervals

MYXEDEMA COMA

Precipitating factors:

• Infections

• Transquilizer, nacrotic analgesic

• Some medications: amiodarone, lithium carbonates, sedatives,

narcotics, anesthesia

• Cold weather

• Other conditions eg. Paralysis, CHF

• An uncommon but life-threatening form of untreated hypothyroidism

with physiological decompensation.

• S&S: hypothermia, advanced stages of hypothyroid symptoms, and

altered sensorium (delirium to coma)

Treatment

99

IV thyroid hormone replacement

T4: 100- to 500-mcg loading dose, followed by 75–100 mcg/day,

until patient can tolerate oral therapy.

Lower the initial dose in frailer patients or in patients with

established cardiovascular disease.

Some advocate the use of T3 over T4, given that T3 is more

biologically active and that T4/T3 conversion may be suppressed in

myxedema coma. Cost and availability limit intravenous T3 use.

Antibiotic therapy: Given common infectious causes, some advocate

empiric therapy with broad-spectrum antibiotics.

Corticosteroid therapy

Hydrocortisone 100 mg q 8 hours (or equivalent steroid)

Can be discontinued if random cortisol concentration not

depressed

Euthyroid goiter

• Goiter without other symptoms and having normal laboratory

value of thyroid hormone, TSH

• Causes:

- Starvation: iodine

- Goitrogenic food, drugs

- Congenital abnormality of thyroid gland

• Treatment:

• Iodine supplement, thyroid hormone

“Goitrogen" is a term used to describe any substance that can cause

enlargement of the thyroid gland

Parathyroid Disorders

• Role of parathyroid glands: control

calcium within the blood

• Four parathyroid glands make more or

less parathyroid hormone (PTH) in

response to the level of calcium in the

blood.

• Increased PTH

• causes body to put more calcium into the blood

• causes the bones to release their calcium into the blood.

Calcium is the most important element for the nervous system,

muscular system, and skeletal system.

Parathyroid• When the calcium in our blood goes too low, the parathyroid

glands make more PTH.

Homeostatic mechanisms to maintain serum calcium concentrations.

Pathology: parathyroid gland

• Hypoparathyroidism

• Pseudohypoparathyroidism

• 1o hyperparathyroidism

• 2o hyperparathyroidism

• 3o hyperparathyroidism

Hypoparathyroidism

• Rare disease

• Most common cause is thyroid gland surgical complication

• other causes are RAI, idiopathic

Signs and Symptoms: Hypocalcemia

- Seizures

- Mental changes: emotional instability

- Parkinson-like movement disorder

- Cardiac conduction abnormalities

- Neuromuscular irritability

- Dry hair, brittle nails, dry & scaly skin

- Calcification: cataract

Diagnosis:

Hypoparathyroidism:

• Hypocalcemia

• Hyperphosphatemia

• Chronic tetany

• Normal alkaline phosphatase

• No CKD, diarrhea

• Increase phosphorous in

urine after PTH is given

Pseudohypoparathyroidism:

• Hypocalcemia

• Hyperphosphatemia

• High level of serum PTH

• Hypoparathyroidism which is

not response to exogenous

PTH

Hypocalcemia

Treatment

• Calcium and vitamin D supplement

Type calcium (mg) Amount (mg) Elemental

Calcium lactate 300 39

Calcium gluconate 500 44.6

Calcium carbonate 250 100

• Initial therapy 1 to 3 g/day of elemental calcium.

• Average maintenance doses range from 2 to 8 g of elemental

calcium per day in divided doses.

• Asymptomatic and chronic hypocalcemia associated with

hypoparathyroidism and vitamin D–deficient states can be managed

by oral calcium and vitamin D supplementation

Hyperparathyroidism• Incidence: In US 100,000 person/year

Female: male =2:1

•Most common age group: 50-70 yrs

• The most common cause is the development of a benign tumor (Familial

endocrine neoplasia type I)

• 95% of patients have one enlarged, overactive gland (single adenoma)

• 1o hyperparathyroidism

– adenoma, hyperplasia, carcinoma – high serum calcium

• 2o hyperparathyroidism

– high PTH from negative feedback mech. in CKD

• 3o hyperparathyroidism

– autonomous parathyroid hyperfunction in secondary

hyperparathyroidism

Sign & Symptoms“MOANS, GROANS, STONES, AND BONES”

• "Psychiatric moans“: effects on CNS including lethargy, fatigue,

depression, memory loss, psychosis, ataxia, delirium, and coma.

• "Abdominal groans“: constipation, indigestion, nausea and vomiting,

GERD (high calcium increase acid production), Pancreatitis

• "Stones" : kidney stones, hypercalciuria, nephrocalcinosis, diabetes

insipidus (polyuria and polydipsia). These can ultimately lead to renal

failure Kidney stone, kidney failure

• "Bones“: Osteoporosis

High BP (75% of patients)

Cardiac symptoms: palpitation, arrhythmia, heart value problem

Headache: recurrent headache

Stroke

Laboratory tests

• Hypercalcemia (>10.5 mg/d)

• Hypophosphatemia

• Hyperchloremia (>102 mEq/L)

• High level of parathyroid

hormone

• Low level of bicarbonate

• High level of cyclic AMP in urine

• X-ray, ultrasound, CT scan

Treatment:

Parathyroidectomy: symptomatic 1๐

hyperparathyroidism

Volume expansion

Furosemide

Pamidronate

Ibandronate

Zoledronate

Calcitonin

Glucocorticoids

Dialysis

Hypercalcemic crisis & acute symptomatic severe hypercalcemia

should be considered medical emergencies and treated immediately

Hypercalcemia: Emergency case

• Hydration: NSS 3-4 L

• Increase excretion: Furosemide IV

• Decrease bone resorption: osteoclast inhibitor:

- Calcitonin 4-8 unit/kg SC q 6-12 hr

- Etidronate 7.5 mg/kg IV

- Plicamycin (cause: cancer): 15-25 mg/kg

• Hydrocortisone 200-300 mg/day

• Dialysis

Drug interactions

• PTU - warfarin, digoxin, theophylline

• MMI - warfarin, digoxin, theophylline

• Levothyroxine – Warfarin, Digoxin

PTU – Warfarin (Moderate): may increase the hypoprothrombinemic response to oral

anticoagulants

PTU- Digoxin (Moderate): clearance of digitalis glycosides may be reduced when a

euthyroid state is achieved after the addition of antithyroid agents.

PTU- Theophylline (Moderate): Clearance of theophylline and related agents

depends upon thyroid function. In the hyperthyroid state, clearance may be

enhanced. In the hypothyroid state, clearance may be reduced.

Levothyroxine – Warfarin (Moderate): Since thyroid hormones may increase the

catabolism of vitamin K-dependent clotting factors, the hypoprothrombinemic

response to oral anticoagulants may be enhanced during the initiation of thyroid

hormone therapy.

Levothyroxine- Digoxin (Moderate): clearance of or sensitivity to digitalis glycosides

may be increased in previously hypothyroid patients when a euthyroid state is

achieved after the addition of thyroid hormones.

Amiodarone and thyroid dysfunction

• Both hypo- and hyperthyroidism are complications of amiodarone therapy

• Meta-analysis of 4 RCTs (n=1465 euthyroid patients):

– prevalence of clinical thyroid disease was higher in patients receiving

amiodarone therapy (150 to 330mg/day for a minimum of one year)

when compared with placebo (3.7% VS 0.4%, respectively) .

• In other reviews and reports,

– Risk of amiodarone-induced thyroid dysfunction ranges from 2 to 30%

depending upon an individual's underlying thyroid status, dietary iodine

intake, and whether cases of subclinical thyroid disorders (eg, slight rise

in thyroid-stimulating hormone [TSH] without symptoms) are included.

Amiodarone and thyroid dysfunction

• Amiodarone contains two iodine atoms.

• Amiodarone metabolism in the liver releases ~ 3 mg of inorganic

iodine into the systemic circulation per 100 mg of amiodarone

ingested.

– Average iodine content in a typical American diet is about 0.3 mg/day.

– Thus, 6 mg of iodine associated with a 200 mg dose of amiodarone

markedly increases the daily iodine load.

• Effects of amiodarone on thyroid function can be divided into

• Effects that are intrinsic properties of the drug

• Effects that are due to iodine

Effects that are intrinsic properties of the drug

• Amiodarone

– inhibits outer ring 5'-monodeiodination of thyroxine (T4),

• thus decreasing triiodothyronine (T3) production; reverse T3

accumulates since it is not metabolized to T2.

• Amiodarone, and particularly the metabolite desethylamiodarone,

– blocks T3-receptor binding to nuclear receptors and decreases

expression of some thyroid hormone-related genes.

• Amiodarone

– may have a direct toxic effect on thyroid follicular cells, which results in

a destructive thyroiditis

Effects due to iodine

• Iodine is a substrate for thyroid hormone synthesis.

• Iodine is actively transported into thyroid follicular cells and organified

onto tyrosyl residues in thyroglobulin.

Management

• Amiodarone-induced hypothyroidism: is essentially the same as for

any patient with hypothyroidism, although higher doses of thyroxine

may be required to normalize the serum TSH level.

• Amiodarone-induced hyperthyroidism (AIT):

–Type I AIT : hyperthyroidism with increased synthesis of thyroid

hormone induced by amiodarone

• Thionamides

–Type II AIT: destructive thyroiditis with loss of TG (thyroglobulin)

and thyroid hormones

• Glucocorticoids