11

2

Maryam Vasheghani , MD

Assistant Professor of Internal medicine _ EndocrinologistNational Research Institute of Tuberculosis and Lung DiseaseShahid Beheshti University of Medical Sciences, Tehran, Iran.

JULY 2015

HYPOTHYROIDISM

33

AGENDA

• Thyroid Gland Anatomy Histology Thyroid Hormone Synthesis, Action and

Metabolism

• Hypothyroidism Epidemiology Clinical presentation Diagnosis Treatment

• Thyroid dysfunction management in patient who is candidate for surgery

Dr. MVasheghani

4

Thyroid Gland

Dr. MVasheghani

55

Thyroid Gland Histology

Dr. MVasheghani

6

Thyroid Hormone Synthesis, Metabolism, and Action

• I : IODINE TRAPPING • Iodide uptake is a critical first step (NIS & Pendrin)

• II : OXIDATION & ORGANIFICATION• The reactive iodine atom is added to selected tyrosyl

residues within Tg.

• III : COUPLING• The iodotyrosines in Tg are then coupled via an ether

linkage in a reaction that is also catalyzed by TPO• MIT + DIT = T3• DIT + DIT = T4

• IV : STORAGE• VI : RELEASE

Dr. MVasheghani 6

77

Regulation of Thyroid Hormone Synthesis

Dr. MVasheghani

88

Worldwide Iodine Nutrition

Dr. MVasheghani

99

HYPOTHYROIDISM

Dr. MVasheghani

1010

DEFINITION

Hypothyroidism is a disorder with multiple causes in which the thyroid fails to secrete an adequate amount of thyroid hormone.

The most common thyroid dysfunction.

Tissue resistance to thyroid hormone:Rare

• Nygaard B.Primary hypothyroidism.Am Fam Physician. 2015 Mar 15;91(6):359-60.PMID: 25822552• Hennessey JV, Espaillat R. Subclinical hypothyroidism: a historical view and shifting prevalence. Int J Clin Pract. 2015

Jul;69(7):771-82. doi: 10.1111/ijcp.12619. • Lane LC, CheethamT, Congenital hypothyroidism – what is new?Paediatrics and Child Health. 2015 Jul ;25( 7): 302-307.

Dr. MVasheghani

1111

CLASSIFICATION• There is different classification:

Congenital or AcquiredPrimary, Secondary or TertiaryOvert or Subclinical Transient or Permanent

• Webb EA, Dattani MT. Understanding hypopituitarism. Paediatrics and Child Health.2015 Jul;25(7 (295-301.

• Doggui, Radhouene; El Atia, Jalila. Iodine deficiency: Physiological, clinical and epidemiological features, and pre-analytical considerations.Annals of Endocrinology . 2015Jul; 76( 1):59-66. © 2015.

• Huang, Chun-Jui; Jap, Tjin-Shing. A systematic review of genetic studies of thyroid disorders in Taiwan.Journal of the Chinese Medical Association. 2015March; 78( 3): 145-153

• Gong G, Basom J. Mattevada S, Onger F. Association of hypothyroidism with low-level arsenic exposure in rural West Texas. Environ Res.2015 Apr;138:154-60. doi: 10.1016/j.envres.

• Zimmermann, Michael B, Prof; Boelaert, Kristien, MD. Iodine deficiency and thyroid disorders.The Lancet Diabetes & Endocrinology.2015; 3( 4): 286-295.

• Peckham S,Lowery D, Spencer S . Are fluoride levels in drinking water associated with hypothyroidism prevalence in England? A large observational study of GP practice data and fluoride levels in drinking water.

• J Epidemiol Community Health. 2015 Jul;69(7):619-24. doi: 10.1136/jech-2014-204971.

Dr. MVasheghani

1212

ETHIOLOGY

Primary Secondary

Dr. MVasheghani

• Insufficient functioning thyroid tissue Autoimmune hypothyroidism

• Hashimoto's or atrophic thyroiditis Iatrogenic

• 131 I treatment, Thyroidectomy, • External irradiation of neck

Infiltrative destruction of thyroid tissue• Amyloidosis, Sarcoidosis, Hemochromatosis,

Scleroderma, Cystinosis, Riedel’s thyroiditis• Impaired thyroid hormone synthesis

Iodine deficiency Overexpression of type 3 deiodinase in infantile

hemangioma and other tumors Drug

• Iodine excess (e.g. iodine-containing contrast media and amiodarone), Lithium, Antithyroid drugs, PAS, INF-α, Aminoglutethimide, TK inhibitors (e.g., sunitinib)

• Hypopituitarism: Tumors Surgery Irradiation infiltrative disorders Sheehan’s syndrome Trauma genetic forms

• Isolated TSH deficiency or inactivity

• Bexarotene treatment• Hypothalamic disease:

Tumors Trauma Infiltrative disorders Idiopathic

1313

ETHIOLOGY CONT…

Transient Congenital

Dr. MVasheghani

• Thyroiditis Silent or postpartum Sub-acute

• Withdrawal of supra-physiologic thyroxin treatment

• Iatrogenic After 131I treatment or subtotal

thyroidectomy for Graves’ disease

• Hypopituitarism: Tumors, surgery or irradiation,

infiltrative disorders, Sheehan’s syndrome, trauma, genetic forms

• Isolated TSH deficiency or inactivity

• Bexarotene treatment• Hypothalamic disease:

Tumors, trauma, infiltrative disorders, idiopathic

1414

EPIDEMIOLOGY

Dr. MVasheghani

• Congenital hypothyroidism occurs in about 1 in 4000 newborns.

• Primary hypothyroidism prevalence ~ 5% of individuals.

• Mild or subclinical hypothyroidism prevalence ~ 15% 6–8% of women (10% over the age of 60)

and 3% of men.

• More common in women. (F/M = 4/1)

• The prevalence of overt hypothyroidism increases with age.

• The annual risk of developing clinical hypothyroidism is about 4% when subclinical hypothyroidism is associated with positive TPO antibodies.

• Secondary hypothyroidism is rare, representing less than 1% of cases.

1515

Congenital Hypothyroidism

Dr. MVasheghani

• Rare• Absent thyroid tissue or hereditary defects in

TH synthesis• Mental retardation due to lack of T4 • It may be associated with:

Autoimmune diseases (Diabetes Mellitus) Cardiomyopathy & CHD Galactorrhoea Muscular dystrophy + pseudohypertrophy (Kocher-

Debre-Semelaigne

1616

Department of Pediatrics, Division of Endocrinology, Oregon Health & Science University, 707 SW Gaines Street, Portland, OR, USA. Congenital hypothyroidismRastogi MV, LaFranchi SH - (2010)

Dr. MVasheghani

1717Prior to Therapy 7 months after therapy

Dr. MVasheghani

18

Diagnosis of CH

Dr. MVasheghani18

1919

1) Azizi F, Janghorbani M, Hatami H, editors. Epidemiology and Control of Common Diseases in Iran. 3rd Ed.Khosravi Publ; 2000. p. 123-39.2) Azizi F, Sheikholeslam R, Hedayati M, Mirmiran P, Malekafzali H, Kimiagar M, et al. Sustainable control ofiodine deficiency in Iran: beneficial results of the implementation of mandatory law on salt iodization. J EndocrinolInvest 2002; 25: 409-13.3)Azizi F, Mehran L, Sheikholeslam R, Ordookhani A,Naghavi M, Hedayati M, et al. Sustainability of a wellmonitored salt iodization program in Iran: marked reduction in goiter prevalence and eventual normalization of urinary iodine concentrations without alteration in iodine content of salt. J Endocrinol Invest 2008; 31: 422-31. 4) Delshad H, Amouzegar A, Mirmiran P, Mehran L, Azizi F. Eighteen years of continuously sustained elimination of iodine deficiency in the Islamic Republic of Iran: thevitality of periodic monitoring. Thyroid 2012; 22: 415-215) Veisani Y, Sayehmiri K, Rezaeian S, Delpisheh A .Congenital Hypothyroidism Screening Program in Iran; a Systematic Review and Metaanalysis. Iran J Pediatr.,201DEC 2014December; 24(6): 665–672.

Dr. MVasheghani

• In 2001 vs 1996 Total goiter rates were 13.9 vs 53.8%, (p<0.0001). Median (range) UIC in 2001 was 165 microg/l and in 1996 was 205 microg/l

(p<0.0001). 1• The goiter rate in the country was 6.5% . The total goiter rate in Hamedan,

Zanjan, Kermanshah, Mazandaran, and Gilan provinces was over 10%.2• According to Meta analysis the overall incidence of Congenital hypothyroidism

was 2/1000 in Iran (95% CI: .002 – .002).3• Elevated TSH levels and low TSH values were found in 8.1% and 3.4% of the

participants respectively. Among those with increased serum TSH, 5.7% had levels between 5.2 – 10 mIU/L and 2.4% had values greater than 10 mIU/L.4

• Congenital hypothyroidism is more prevalent in iran (2/1000 live births) .5

Epidemiology of Hypothyroidism in IRAN

20

Karimi F, Kalantarhormozi MR, Dabbaghmanesh MH, Ranjbar Omrani G.Thyroid disorders and the prevalence of antithyroid antibodies in Shiraz population Arch Iran Med. 2014 May;17(5):347-51. doi: 0141705/AIM.008.

Dr. MVasheghani20

2121

Karimi F, Kalantarhormozi MR, Dabbaghmanesh MH, Ranjbar Omrani G.Thyroid disorders and the prevalence of antithyroid antibodies in Shiraz population Arch Iran Med. 2014 May;17(5):347-51. doi: 0141705/AIM.008.

Dr. MVasheghani

2222

Thyroid Disease Spectrum

0 105

TSH, IU/mL

Subclinical HypothyroidismTSH >4.7 IU/mL, Free T4 Normal

Overt HypothyroidismTSH >4.7 IU/mL, Free T4 Low

EuthyroidTSH 0.5-4.7 IU/mL, Free T4 Normal

HyperthyroidismTSH <0.5 IU/mL, Free T3/T4 Normal or Elevated

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.Dr. MVasheghani

23

EVALUATION• History & Physical Examination• Measurement of Thyroid Hormones

TSH assays Total T4 and total T3

Unbound thyroid hormones T3RU

• ↑ T3RU in hyperthyroidism and ↓ TBG Free T3 or free T4 index = total T4 or T3 concentration

x the thyroid hormone binding ratio (THBR)• Tests to Determine the Etiology

Antibodies against TPO and Tg ,TSI Serum Tg

• Radioiodine Uptake and Thyroid Scanning• Thyroid Ultrasound• Fine-Needle Aspiration (FNA) biopsyDr. MVasheghani 23

2424

Thyroid-Stimulating Hormone Assays

Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.Zophel K, et al. Nuklearmedizin. 1999;38:150-155.Dr. MVasheghani

• Key test for diagnosis of hypothyroidism and hyperthyroidism

• TSH assay sensitivity has improved with subsequent test generations First generation: RIA

• Sensitivity: 1.0 IU/mL Second generation: IRMA

• Sensitivity: 0.1 IU/mL Third generation: ELISA

• Sensitivity: 0.03 IU/mL Chemiluminescence immuno assay : CLIA

• Gold standard ,Sensitivity: 0.001 IU/mL

2525

What the mind knows the What the mind knows the eyes see !!eyes see !!

• Other Autoimmune disease

• Rx. Grave’s Ophthalmopathy

• Family Hx. thyroid disease

• Neck irradiation therapy

• Previous Rx for thyrotoxicosis

• Autoimmune Thyroiditis

• Chronic urticaria

Order for TSH alone as a screen test

Dr. MVasheghani

• Psychiatric patients

• Elderly women / men

• Patients of OSA

• Hypercholesterolemia

• Lithium, Amiodarone

• Postpartum women

Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.Carmel R, et al. Arch Intern Med. 1982;142:1465-1469.Perros P, et al. Diabetes Med. 1995;12:622-627.

26

Screening for Disorders of Thyroid Function

DisorderPrevalence in AdultsScreening Recommendation

Hypothyroidism5–10%, women0.5–2%, men

TSH; confirm with free T4 Screen women after age 35 and

every 5 years thereafter

Graves’ disease1–3%, women

0.1%, menTSH, free T4

Thyroid nodules and neoplasia

2–5% palpable>25% by ultrasound

Physical examination of thyroidFine-needle aspiration biopsy

Hyperparathyroidism0.1–0.5%,

women > men

Serum calcium PTH, if calcium is elevated

Assess comorbid conditions

Table 399-2 The Principle of Internal Medicine, Harrison 19 th editionDr. MVasheghani26

27Dr. MVasheghani

27

Autoimmune Hypothyroidism

28

Hashimoto's thyroiditis (chronic autoimmune thyroiditis) is the most common cause of hypothyroidism in iodine-sufficient areas of the world. It is characterized clinically bygradual thyroid failure, goiter, or both, due to autoimmune-mediated destruction of the thyroid gland. Nearly all patients have high serum concentrations of antibodies againstone or more thyroid antigens, lymphocytic infiltration of the thyroid, which includes thyroid-specific B and T cells, and apoptosis of thyroid follicular cells.

Chronic Autoimmune Thyroiditis

Dr. MVasheghani28

29

Grave’s Disease Hashimoto Disease

Postpartum thyroiditis

Silent thyroiditis

Drug induced thyroiditis

Spectrum of thyroid autoimmunity

Dr. MVasheghani29

30

Possible precipitating factors

Dr. MVasheghani30

• Genetic

• Gender: Women have more risk.

• Age: Elderly

• Infection

• Stress

• Humoral factors (sex steroids , pregnancy)

• Prior history of Graves disease or postpartum thyroid dysfunction

• Other autoimmune disease Pernicious anemia Type 1 Diabetes mellitus

• Family history of thyroid disease other autoimmune disease• Laboratory evidence of hypercholesterolemia, elevated LFTs,

elevated CPK and LDH

31

Pathogenesis

Molecular mimicryBystander activationThyroid cell expression of HLA AgThyroid cell apoptosis

Dr. MVasheghani31

• Thyroid auoantigenes• Role of B cells• The primary role of T cells• Potential mechanism of thyroid

injury

32

•The disease clusters in families, sometimes alone and sometimes in combination with Graves' disease • It is more common in women.• The concordance rate in monozygotic twins is 30 to 60 percent. • It occurs with increased frequency in patients with Down's and Turner's syndrome.• There is an association, albeit relatively weak, with certain HLA alleles.• There is an association with certain alleles of the gene for CTLA-4, a T-cell surface molecule

involved in T-cell activation Dr. MVasheghani

32

33Dr. MVasheghani

33

34Dr. MVasheghani

34

35Dr. MVasheghani

35

36 36

TFT in Progressive Hypothyroidism

TSH

Moderate SevereMild

Normal Range

Free T4Free T3

36

37Dr. MVasheghani

37

38

The characteristic histopathological abnormalities are profuse lymphocytic infiltration, lymphoid germinal centers, and destruction of thyroid follicular cells .fibrosis and areas of follicular-cell hyperplasia, presumably induced by TSH, are also seen in patients with severe disease. The intrathyroidal lymphocytes are both T and B lymphocytes.

PATHOLOGY

Dr. MVasheghani38

39Dr. MVasheghani

39

4040Dr. MVasheghani

4141

Clinical Features of Hypothyroidism

• Hypothyroidism is insidious in onset and the most of symptoms or signs are nonspecific in nature, these make it difficult to diagnose. Symptoms that are new, progressive, or present in combination are more likely to be due to hypothyroidism.

• Moreover, hypothyroidism S&S vary according to the age at onset and disease severity.

Dr. MVasheghani

42

CURRENT CLINICAL PICTURE

• The prevalence of hypothyroid patients presenting with minimal symptoms is increased, largely due to the availability of sensitive and specific laboratory tests that allow recognition of the primary form of the disease long before severe symptoms have developed.

42Dr. MVasheghani

43

Figure 12-5  Frequency of hypothyroid symptoms and signs (%) overt hypothyroidism and controls

43Dr. MVasheghani

44

Causes of clinical S & S• The mechanisms of S & S are:

Slowing of metabolic process Accumulation of matrix substance

• The clinical features of disease are the consequence of: Thyroid hormone deficiency Thyroid autoimmunity Associated with signs or symptoms of other

autoimmune diseases, particularly Vitiligo, PA, Addison’s disease, Alopecia areata, and T1DM

44Dr. MVasheghani

45

Multisystem effects of Hypothyroidism

• GeneralTirednessWeakness and FatigueCold Intolerance (Feeling cool)Lethargy, SomnolenceWeight gain with poor appetite

• The weight gain is usually modest and due mainly to fluid retention in the myxedematous tissues.

• Typical features (myxedema) include a puffy face with edematous eyelids and nonpitting pretibial edema .

45Dr. MVasheghani

46

Skin and Hair

46Dr. MVasheghani

• Thickening, flayking and dryness of skin Decreased sweating

Thinning of the epidermis

Hyperkeratosis of the stratum corneum.

Increased dermal glycosaminoglycan (myxedema)

Content traps water, giving rise to skin thickening without pitting

• Dry, coarse hair, Alopecia

• Loss of lateral eyebrow hair (thinning of the outer third of the eyebrows)

• Pallor, often with a yellow tinge to the skin due to Carotenimia.

• Nail growth is retarded and brittle.

• Blood flow is diverted from the skin, producing cool extremities. Myxoedema, Malar flushes, Vitiligo

47

Head and Neck

47Dr. MVasheghani

• Impaired hearing due to Conductive deafness

• Hoarse voice• Thick, slurred (clumsy) speech and are

due to myxedematous infiltration of the tongue and larynx, respectively.

• Ophthalmopathy occurs in about 5% of pts with autoimmune hypothyroidism

48

Cardiovascular

48Dr. MVasheghani

• Dyspnea, Angina • Decreased ventricular contractility, CHF• Increased diastolic blood pressure• Narrow pulse pressure

Reduced stroke volume Increased peripheral resistance

• Bradycardia• Peripheral non-pitting edema

• Pericardial effusions occur in up to 30% of patients but rarely compromise cardiac function.

• Alterations in myosin heavy chain isoform expression have been documented ,but cardiomyopathy is unusual.

• HyperlipIdemia, Xanthelsma

49

Respiratory system

49Dr. MVasheghani

• Pulmonary function is generally normal.• Dyspnea may be caused by

Pleural effusion Impaired respiratory muscle function Diminished ventilatory drive Sleep apnea

50

Gastro-intestinal Tract

50Dr. MVasheghani

• Gastro-intestine Constipation, fecal impaction (myxedema

megacolon). Ileus, Decreased GI motility, Gaseous distention Ascites Achlorhydria Elevations in the serum levels of CEA Malabsorption

• Hepatic Increased LDL / TC Elevated LDL + triglycerides Levels of aminotransaminases may be elevated The gallbladder contracts sluggishly and may be

distended

51

Genito-Urinary system

51Dr. MVasheghani

• Renal

• Fluid retention and oedema

• Decreased GFR

• Reproductive system

• Infertility, ↑ Miscarriage

• Menometrorrhagia, oligomenorrhea or amenorrhea

• Impotence, ↑ Prolactin

• ↓ Libido both sexes

• Premature ovarian failure

52

Musculoskeletal

52Dr. MVasheghani

• Muscle stiffness, cramps, pain, weakness, myalgia

• Slow muscle-stretch reflexes, muscle enlargement, atrophy

• Carpel tunnel syndrome• arthralgias• Pseudomyotonia

• Slow relaxation of DTR

• Arthralgias,

53

Central Nervous System

53Dr. MVasheghani

• Memory and concentration impairment• Depression with limited initiative and sociability.• Cognitive deficits can range from mild lapses in

memory to delirium, dementia, seizures, psychosis, and myxedema coma

• Cerebellar ataxia, myotonia, paresthesias• Hashimoto’s encephalopathy has been defined as a

steroid-responsive syndrome associated with TPO antibodies, myoclonus, and slow-wave activity on electroencephalography

54

Clinical Signs of Hypothyroidism

•Coarse Hair; Diffuse thinning of scalp hair •The skin may be coarse, dry, pale or yellow and cool due to peripheral vasoconstriction; Brritle nails

•Thinning of lateral 1/3 of eye brows (Queen Anne sign)

•Puffiness of eyes and face

Goiter (not in all cases), the thyroid gland may be normal in size, diffusely enlarged, or atrophic, It may be soft and smooth with a lobular texture, or firm and irregular with a variegated nodular texture ; cervical incisional scars •Low hoarse speech and slow movements; slow and dysarthric speech•Bradycardia, pericardial effusion, diastolic hypertension, Non-pitting edema (myxoedema), ↓ heart sound•Delayed relaxation of DTR with a marked delay in the terminal relaxation phase (Hang up reflex)

54Dr. MVasheghani

55

Abnormal laboratory in hypothyroidism• Anemia (25-50% of patients)• Hyponautremia• Hypercholesterolemia (90% of patients)

14% of patients hypercholesterolemia have hypothyroidism

• Abnormal LFT• Elevated CPK and LDH• Hyperprolactinemia• Decreased GH secretion and action• Schmidt syndrome (Primary adrenocortical insufficiency)

Dr. MVasheghani55

5656Dr. MVasheghani

5757Dr. MVasheghani

58

Clinical features

58Dr. MVasheghani

5959Dr. MVasheghani

Pretibial Myxedema Myxedema with Carotinemia

6060

Pituitary Tumor – Secondary Hypo

Normal Pituitary Fossa

Dr. MVasheghani

61

Massive Pericardial Effusion

61

Feb1998

Dr. MVasheghani

Sep 1998 Dec1999

6262Dr. MVasheghani

63

Before Therapy After Therapy

Dr. MVasheghani63

6464Dr. MVasheghani

Before Therapy After Therapy

65

Hypothyroidism and DepressionHave Many Common Features

Depression

• Sleep decrease• Suicidal ideation

• Weight loss• Appetite increase/

decrease

Nemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20.

• Bradycardia• Cardiac and lipid

abnormalities• Cold intolerance• Delayed reflexes

• Goiter• Hair and skin

changes

• Constipation• Appetite decrease

• Decreased concentration• Decreased libido

• Delusions• Depressed mood

• Diminished interest• Sleep increase

• Weight increase• Fatigue

Hypothyroidism

Dr. MVasheghani65

6666Dr. MVasheghani

67

Classification

67Dr. MVasheghani

• Established reference ranges for TSH levels is 0.5 to 4.5 mIU/L.

• A low free T4 level with a persistently elevated TSH level represents overt primary hypothyroidism.

• A low-normal free T4 level with an elevated TSH level is termed mild or subclinical primary hypothyroidism.

• Other uncommon causes of isolated TSH elevation include: Recovery from severe systemic illnessRenal failureAdrenal insufficiency.

68

TFT ASSESSMENT

68Dr. MVasheghani

6969

Condition that affect TSH level

Low serum TSH

Dr. MVasheghani

Primary hyperthyroidismIncomplete recovery of hyperthyroidismNTIHigh level of hCG, early pregnancy, molar pregnancy, coriocarcinomaDrugs: dopamine agonist, GC, somatostatin analogsCentral hypothyroidism

Primary hypothyroidism Recovery from NTI Drugs: dopamine antagonist,

amiodarone, OCG dye TSH-producing pituitary

adenoma Adrenal insufficiency Heterophilic antibody

interference Generalized thyroid hormone

resistant

High serum TSH

70

• The underlying cause of primary hypothyroidism is usually clinically

obvious, and laboratory testing is unnecessary in most cases.

• When confirmation is required (e.g., to convince a patient the

condition is permanent), serum antithyroid antibodies may be

assessed. Measurement of Anti-TPO Ab is a more sensitive test

than Anti-Tg Ab for this purpose.

• However, 10% of patients with histologically documented

autoimmune thyroiditis have no circulating antithyroid antibodies.

70Dr. MVasheghani

7171

• When clinical findings suggest the possibility of secondary hypothyroidism such as: The presence of a sellar massPrevious pituitary surgery or irradiationOther pituitary axis hormone deficiencies

• The serum TSH and free T4 level must be assessed. • In these settings, a low or even low-normal free T4 level

can confirm the diagnosis. • The TSH level in patients with secondary hypothyroidism

can be low, normal, or even modestly elevated.

Dr. MVasheghani

72

Diagnosis

72Dr. MVasheghani

73

Treatment

73Dr. MVasheghani

•The goals of thyroid hormone replacement therapy are: To replace endogenous thyroid hormone productionTo avoid iatrogenic thyrotoxicosisTo treat systemic complications of severe hypothyroidism, rarely.

•Therapy with levothyroxine sodium products requires individualized patient dosing:

Careful titration: use a formulation with consistent dosesClinical evaluation: symptoms resolve more slowly than TSH responseLaboratory monitoring: need consistent, sensitive TSH measurements

74

Treatment

74Dr. MVasheghani

• Treatment depends upon :

Cause and severity of disease

Patients age and weight

Goiter size

Comorbid states and treatment

Cardiovascular health

75

• LT4, LT3 or LT4+LT3

• LT4 therapy Choice

• LT4+LT3 therapy Sometimes

• Is there any place for liothyronine

alone as long-term replacement?

75

NO ‼

Dr. MVasheghani

7676Dr. MVasheghani

1.6 micg/kg BW, at least 30 min before breakfast.

The goal of treatment being a normal TSH, ideally in the lower half of the reference range.

TSH should be measured 4 - 8 week later.

Once an adequate dose has been established, the TSH level should be checked annually.

In patients with secondary hypothyroidism, the serum free T4 level should be monitored 2 to 4 weeks after the thyroxine dose is started or adjusted, with a target free T4 level in the upper half of the reference range.

Clinical Hypothyroidism

77

Thyroid hormone replacement

• Levothyroxine sodium is choice.

• It is well absorbed and 7 day half-life.

• Thyroxine is physiologically deiodinated to the more biologically active T3 in peripheral tissues.

• Thyroxine has a narrow therapeutic index, and doses differing by as little as 12% can have clinicalconsequences.

• Bioavailability may differ by as much as 12% among different preparations. Consequently, adherence to a single thyroxine formulation is advisable.

77Dr. MVasheghani

2004 AACE, TES, and ATA Joint Position Statement on the Use and Interchangeability ofThyroxine Products

7878

Primary Hypothyroidism Rx. Algorithm

TSH >3.0 IU/mL TSH <0.5 IU/mL

Initial Levothyroxine Dose

IncreaseLevothyroxine

Dose by12.5 to 25 g/d

Repeat TSH Test

6-8 Weeks

TSH 0.5- 2.0 IU/mLSymptoms Resolved

Measure TSH at 6 Months, Then Annually or

When Symptomatic

Continue Dose DecreaseLevothyroxine

Dose by12.5 to 25 g/d

Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds. The National Academy of

Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed

July 1, 2003.Dr. MVasheghani

79

CONT…

• In patients of normal body weight who are taking 200 g of levothyroxine per day, an elevated TSH level :Poor adherence to treatment.Malabsorption (e.g., celiac disease, small-bowel surgery)Drug:

• Estrogen or selective estrogen receptor modulator therapy, Lovastatin, Amiodarone. PPI, TK inhibitors

Thyroxine doses should be separated from these substances by 8 hours or longer

Ingestion with a meal

Dr. MVasheghani79

80

Interfrence with LT4 replacement

80Dr. MVasheghani

81

• The clinical effects of levothyroxine replacement are slow to appear. Patients may not experience full relief from symptoms until 3–6 months after normal TSH levels are restored.

• patients who miss a dose can be advised to take two doses of the skipped tablets at once.

81Dr. MVasheghani

82

What is a Normal TSH?• In their 2002 position statement, AACE used an

upper limit of normal for TSH of 3.0mIU/L established in a population of patients carefully screened for thyroid disease by the National Academy of Biochemistry in 2002.

• However, in 2004 a statement was published in JAMA maintaining that the upper limit of TSH should remain at 4.5 mIU/L, rather than 3.0-3.5 as some other organizations have suggested.

82

AACE MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE EVALUATION AND TREATMENT OF HYPERTHYROIDISM AND HYPOTHYROIDISM. ENDOCRINE PRACTICE Vol 8 No. 6 2002JAMA 2004; 291:228-238

Dr. MVasheghani

83

Complications Pseudotumor cerebri in children

• Idiosyncratic and occurs months after treatment has begun.

Thyrotoxicosis usually accompany significant degrees of overtreatment

Bone mineral loss, especially in postmenopausal women

Increase the risk of AF in older individuals, even a modestly excessive thyroxine

dose

Exacerbate myocardial ischemia in patients with underlying CAD

Coexisting adrenal insufficiency may be unmasked.

Transient hair loss

Acute sympathomimetic symptoms

83Dr. MVasheghani

84

Subclinical Hypothyroidism

• Subclinical hypothyroidism refers to biochemical evidence of thyroid hormone deficiency .

• An isolated elevated TSH level with normal T3 and T4 levels • It is important to confirm that any elevation of TSH is

sustained over a 3-month period before treatment is given.• There are no universally accepted recommendations for the

management of subclinical hypothyroidism.• Treatment is administered by starting with a low dose of

levothyroxine (25–50 μg/d) with the goal of normalizing TSH.

84Dr. MVasheghani

85

Subclinical Hypothyroidism

• Who should be treated? Patient is symptomatic

TSH levels >=10 mU/L.

TPO antibodies positive

Woman who wishes to conceive or is pregnant

Any evidence of heart disease

• Maintain TSH in normal range• In patients not receiving Levothyroxine therapy,

check TSH every 3-6 months(annually) or when symptoms occur

85Dr. MVasheghani

86

Special Treatment Considerations• Women should ensure that they are euthyroid prior to

conception and during early pregnancy.

• The dose of levothyroxine may need to be increased:

↑ dose 50%(25-75%) during pregnancy

Post-surgical or post-Iodine ablation

Nephrotic syndrome due to rapid clearance of thyroid hormone

• The dose of levothyroxine may need to be decreased:

↓ Dose 20% in elderly patients

Adults with known or suspected ischemic heart disease

86Dr. MVasheghani

87

Hypothyroidism & Pregnancy

• Fetal neural development delay or preterm delivery. • The presence of thyroid autoantibodies alone, in a euthyroid pt,

is associated with miscarriage and preterm delivery.• TFT should be evaluated immediately and every 4 w during the

first half of the pregnancy, then every 6–8 w depending on whether LT4 dose adjustment is ongoing after 20 W gestation.

• The goal TSH of less than 2.5 mIU/L during the first trimester and less than 3.0 mIU/L during the second and third trimesters.

• After delivery, LT4 doses return to pre-pregnancy levels. • Pregnant women should be separate ingestion of prenatal

vitamins and iron supplements from LT4 by at least 4 h.

87Dr. MVasheghani

88

Hypothyroidism & Heart Disease

• Elderly patients may require 20% less thyroxine than younger patients.

• The starting dose of levothyroxine is 12.5–25 μg/d with similar increments every 2–3 months until TSH is normalized.

• In some patients, it may be impossible to achieve full replacement despite optimal antianginal treatment.

88Dr. MVasheghani

89

Hypothyroidism & Surgery• Emergency surgery is generally safe in

patients with untreated hypothyroidism.

• Elective or routine surgery in a hypothyroid patient should be deferred until euthyroidism is achieved.

89Dr. MVasheghani

90

Hypothyroidism Following Hemithyroidectomy

• The incidence & risk factors for hypothyroidism in patients undergoing partial thyroid surgery remains unclear. With reported incidence of b/w 6.5% & 45% and up to 65% in patient with head and neck ca .

• Risk factors are the presence of :Anti-TPO antibody Thyroiditis in pathologyMultinodular goiterPreoperative thyrotoxicosisThyroid remnant < 6 gElderly patients

90Dr. MVasheghani

91DAMAVAND MOUNTAIN

TEHRAN , IRAN