Thyroid Diseases

Q1: The most common thyroid function disorder is?

• 1) Graves’ disease• 2) Hypothyroidism• 3) Sub-acute thyroiditis• 4) Thyroid cancer

Q2: The most sensitive test for thyroid function is?

• 1) Free T4• 2) Free T3• 3) TSH• 4) Thyroid ultra sound

Q3: The best assay to confirm that a patient’s hypothyroidism is autoimmune in nature?• 1) Thyroid stimulating

immunoglobulins• 2) Anti-nuclear antibody• 3) TSH• 4) Thyroid peroxidase antibodies

Q4: The best assay to confirm that a patient’s hyperthyroidism is autoimmune in nature?• 1) Thyroid stimulating

immunoglobulins• 2) Anti-nuclear antibody• 3) TSH• 4) Thyroid peroxidase antibodies

Q5: Which is the best study to confirm the etiology of a patient’s thyrotoxicosis?

• 1) I123 thyroid scan/uptake• 2) Neck CT or MRI • 3) Thyroid ultrasound• 4) Fine needle aspiration of the

thyroid

Q6: Which is the best study to make the initial evaluation for thyroid nodules discovered on routine physical exam?

• 1) I123 thyroid scan/uptake• 2) Neck CT or MRI • 3) Thyroid ultrasound• 4) Fine needle aspiration of the

thyroid

Q7: Patient has a thyroid U/S showing a solid dominant (>10mm) nodule and normal thyroid function, what is your next step?

• 1) Re-check thyroid U/S in 1 year • 2) Fine needle aspiration of the

thyroid • 2) Neck CT or MRI • 4) I123 thyroid scan/uptake

Q8: Thyroid U/S shows homogeneous increased radiotracer uptake, the diagnosis is?• 1) Metastatic thyroid cancer• 2) Graves’ disease• 3) Toxic multi-nodular goiter• 4) Toxic thyroid nodule

Q9: Methimazole or propylthiouracil and used to treat hypothyroidism?

• 1) True• 2) False

Q10: Which is not an appropriate treatment for Graves’ disease?

• 1) Thyroidectomy• 2) Anti-thyroid medications such

as propylthiouracil or methimazole

• 3) Levothyroxine sodium • 4) I131 radioactive iodine

Follicular cells arranged in clumps. Clumps of cells contain colloid. Colloid an iodine containing protein

called thryoglobulin. This is the precursor and storage form of thyroid hormone.

Thyroxine (T4), Triiodothyronone (T3)

Synthesis and Secretion

T4 and T3 circulate in the blood bound to plasma proteins.

TBG(70%), TBPA(20%) and albumin(10%).

T3 is the active form, 5 times more active than T4.

T4 is converted to T3 outside the thyroid, mostly in liver and kidney.

T3 binds to a nuclear receptor

Thyroid hormone action

T4 and T3 circulate in the blood bound to plasma proteins.

TBG(70%), TBPA(20%) and albumin(10%).

T3 is the active form, 5 times more active than T4.

T4 is converted to T3 outside the thyroid, mostly in liver and kidney.

T3 binds to a nuclear receptor

Thyroid hormone action

TRH secreted from hypothalmus controls TSH production.

TSH from anterior pituitary stimulates secretion of T4 and T3 from thyroid.

Regulated by a negative feedback loop.

Regulation of the H-P-T axis

Major Thyroid Abnormalities

Functional / Biochemical• Hypothyroidism• Hyperthyroidism

Structural / Anatomy

• Thyroid– Goiter

– Nodules• Cold• Warm or Hot

– Cysts– Malignancies

At Risk Population for Thyroid Dysfunction

• Women, elderly, postpartum 4-8 months.• FamHx of Hashimoto’s or Graves’ dz.• PMHx or FamHX autoimmune diseases –

SLE, RA, DM1, Addison’s, vitiligo, pernicious anemia.

• Type 1 DM: ~20% increase risk for thyroid dysfunction, mainly hypothyroid.

• Patients treated with amiodarone, lithium, others

HYPOTHALAMIC / PITUITARY THYROID AXIS

• TRH: stimulate anterior pituitary to release TSH.

• TSH: stimulate thyroid for synthesis and release of T4 and T3.

• Low T4, Low T3: stimulate TSH and TRH.

• High T4, High T3: inhibit TSH and TRH.

THYROID HORMONES

• T4 to T3 secretion ratio of 10:1.• T3 is 4X more biologically active than

T4.• T1/2: T4 = 7days, T3 = 1 day.• T4,T3: 99% bound to protein, i.e.

metabolically inactive.• From thyroid: 100% - T4, 20% - T3

remainder of T3 is from T4 to T3 conversion in peripheral tissues.

THYROID TESTINGBiochemical

TSH - highly sensitive, best test for thyroid function.

1) Free T4 (FT4)- biologically active.

2) Free T3 (FT3) - biologically active.

- rarely need to check unless, TSH is low or undetectable with a normal FT4.

THYROID TESTING(more specific)

• Thyroid Peroxidase Antibodies (TPO-Ab’s) - Hashimotos Thyroiditis• Thyroid Stimulating Immunoglobulins (TSI’s)

or TSH receptor antibodies (TRAb). - Unique to Graves’ disease• I-123 RAIU (Radio Active Iodine Uptake)

evaluation for thyrotoxicosis, shape, size. Don’t use to confirm hypothyroidism.

DON’T FORGET THE BASICS

• History of present illness and ROS.• PMHx – postpartum

– Past Hx of thyroid pain/tenderness/nodule/ enlargement or goiter

– H/O autoimmune diseases• FamHX – thyroid dysfunction, thyroid

cancer, Autoimmune diseases.• Medications• Systematic physical exam

Hypothyroidism

HYPOTHYROIDISM

• Prevalence: 4 - 8% general population.

• Mean age of Dx: 5th decade of life• Female to male ratio: 10:1

Hypothalamic disease Pituitary disease

Secondary hypothyroidism-causes

PRIMARY HYPOTHYROIDISM

• Identification on clinical basis can be challenging.

• Symptoms generally vague.• Frequently goes unnoticed, confused as

other health problems.• Insidious onset + poor index of

suspicion = misdiagnosis

ETIOLOGY

• Autoimmune:

- Chronic lymphocytic thyroiditis = Hashimoto’s

- positive TPO-Ab’s

- remember postpartum thyroiditis • Iatrogenic: I-131 RAI, total/subtotal

thyroidectomy, neck irradiation.• Congenital: agenesis, dysgenesis.• Drug induced: lithium, amiodarone,

chemotherapy, others.

Clinical Symptoms of Hypothyroidism

• Fatigue• Lethargy• Cold intolerance • Constipation• Decreased

memory• Depression• Mental

Impairment

• Arthralgias • Hoarseness• Heavy menstrual

flow• Paresthesias• Sleepiness• Weight

gain ,edema• Muscle cramps

Clinical Signs of Hypothyroidism

• Bradycardia• Coarse hair, hair loss• Delayed relaxation phase of deep tendon reflexes• Dry, cool, pale skin• Goiter• Hoarseness• Non-pitting edema (myxedema)• Puffy eyes and face• Slow movements• Slow speech• Thinning lateral third of eyebrows

Example of Clinical Manifestationsof Hypothyroidism

• Patient example– Fatigue (“no energy”), cold

intolerance, constipation, weight gain, fatigue, problems with concentration (“mental clouding”), dry skin

CLINICAL MANIFESTATONSEXAM

• NECK: thyroid may be normal, enlarged, symmetric/asymm., smooth or lumpy.

• HEART: bradycardia.• EXTREMS: pretibial/ankle edema, dry

cool skin, brittle nails.• NEURO: DTR’s with delayed relaxation

phases• HEENT: periorbital puffiness, loss of

lateral eyebrows, coarse/thinning hair.

Dry skin Erythema ab igne Vitiligo

Infertility Menorrhagia Galactorrhoea

Clinical FeaturesSkin and Reproduction

Aches and Pains Carpal Tunnel Deafness Hoarseness Ataxia Depression Psychosis

Iron deficiency A Pernicious Anemia

Clinical FeaturesNeurological and Haematological

LABORATORY EVALUATION

• TSH - high • Free T4 - low• Check both if new diagnosis to make

sure PITUITARY-THYROID AXIS intact.

• Consider TPO-Ab

Fasting cholesterol and triglycerides may be raised

Ck AST and LDH (SMAC 20) may be raised

FBC Anemia ECG Slow rate. Small complexes.

Additional abnormal tests.

Levothyroxine Sodium (LT4 )

• Exogenously administered LT4 hormone• Indistinguishable from endogenous T4,

both in its physiologic effects and its quantification as measured in blood

• LT4 is the treatment of choice as replacement or supplemental hormone therapy

• Branded preparations are preferred

TREATMENT • Levothyroxine (LT4), narrow

therapeutic range– 0.3 – 3.0 IU/mL, caution

in lower range TSH.• Brand vs. generic vs. T4 + T3

combination.• Lifelong treatment, most

cases• Dosing: 1.6 mcg/kg/day =

~100 - 125 mcg/day.• Compliance, empty stomach,

competing agents for absorption (Iron, Calcium )

• Check TSH no sooner than 6 weeks after initial start of LT4 or any adjustment.

Therapy Monitoring

• Clinical and laboratory monitoring enable– Evaluation of the clinical response– Assessment of patient compliance– Assessment of drug interactions, if applicable– Adjustment of dosage, as needed

• Clinical and laboratory evaluations should be performed – At 6- to 8-week intervals while titrating– Annually once a euthyroid state is established

Factors That May Reduce Levothyroxine Effectiveness• Malabsorption Syndromes

– Post jejunoileal bypass surgery

– Short bowel syndrome– Celiac disease

• Reduced Absorption– Colestipol

hydrochloride – Sucralfate– Ferrous sulfate– Food (eg, soybean

formula)– Aluminum hydroxide– Cholestyramine– Sodium polystyrene

sulfonate

• Drugs That Increase Clearance– Rifampin– Carbamazepine– Phenytoin

• Factors That Reduced T4 to T3 Clearance– Amiodarone– Selenium deficiency

• Other Mechanisms– Lovastatin– Sertraline

Thyroid Hormone TherapySpecial Treatment Populations

• Patients 50 years of age or with underlying cardiac disease– Initial dose of LT4 - 25 to 50 mcg/d

• Elderly patients with cardiac disease– Initial dose of LT4 - 12.5 to 25 mcg/d

• Patients with heart failure– Both hypo- and hyperthyroidism can

worsen heart failure

Treating Hypothyroidism Before and During Pregnancy

• Encourage adherence with LT4 replacement therapy before conception

• Monitor TSH levels before conception and during first trimester

• Consider increase of LT4 dosage in athyreotic patients by 25% - 50% when pregnancy is confirmed

• Monitor TSH levels every 6 to 8 weeks throughout pregnancy

• Reinstate pre-pregnancy LT4 dosage immediately following delivery

Over-Replacement Risks

• Switching a narrow therapeutic index drug, such as LT4, without retesting and re-titrating can cause inconsistent TSH control, resulting in over-replacement

• Over-replacement risks (TSH <0.5 IU/mL)

– Iatrogenic thyrotoxic state– Increased heart rate and myocardial contractility– For cardiac patients, increased risk of angina and MI– Reduced bone density/osteoporosis– Psychiatric symptoms, such as anxiety, sleep

disturbance, irritability, and fatigue

Case 1

46 y.o. female presents with a 3 - 4 month history of heavier than usual menstrual cycles, fatigue, “feeling sleepy all of the time”, depressed, constipation, problems concentrating, cold intolerance.

• PMHx: unremarkeable• FAMHx: Adopted.

Case 1 continued

• P.E. : DTR’s show delayed relaxation phases of biceps and brachioradialis, non tender symmetric goiter @ 2 times normal size without nodules.

• LABS : TSH 77.02 (0.45-4.50) Free T4 0.38 (0.8 – 1.50)

TPO-Ab 267 reactive greater 40.

Case 1 continued

• Dx: Hashimoto’s Thyroiditis• Tx: 100 mcg qd, non-generic LT-4 Follow-up in 6 weeks and recheck TSH• F/U: Feeling “90% better”

TSH 7.62 Increase to 112mcg qd. Follow-up in 2 months.

• 2 months later TSH – 2.11 (0.50 - 3.00). Plan: follow and adjust LT-4 based on TSH

SUBCLINICAL HYPOTHYROIDISM

• Very difficult to diagnose clinically• High index of suspicion, may be asymptomatic• 4 -15% of general population*• 20% of pts. over 60 y.o. (esp. women)**• LABS: TSH - minimally high (6 - 10 IU/mL) Free T4 – low normal• TREATMENT: controversial, consider if

symptoms, lipid abnormality, if TPO-Ab positive

• Low dose LT-4 vs. surveillance, education.

Mild Thyroid Failure and Neurobehavioral Abnormalities

• Conditions reported to occur more frequently in patients with mild thyroid failure – Depression– Anxiety– Somatic complaints– Cognitive abnormalities

Rationale for Treating Mild Thyroid Failure

• Potential benefits from treatment– Prevent progression to overt

hypothyroidism– Improve serum lipid profile, which

may reduce the risk of death from cardiovascular causes

– Reduce symptoms, including psychiatric and cognitive abnormalities

Repeat tests after an interval. If TSH is continuing to rise in the presence

of strongly positive antibodies, the risk of developing hypothyroidism in the future is high. Thus treatment with thyroxine at this early stage may be justified if symptomatic.

Beware-Thyroxine may not cure all symptoms.

Treatment

Case 2

• Hx: 32 y.o. women referred for mildly increased TSH 8.69 (0.46-4.68)

• Symtoms: mild fatigue, dry skin, “not feeling my usual self”

• PMHx: no H/O thyroid disorders, or recent of remote thyroid pain/tender.

• FAMHx: Mother, two maternal aunts with hyperthyroidism.

Case 2 continued

• P.E. : Thyroid minimally enlarged and non-tender, no nodules. remainder of exam unremarkable.

• Labs: TSH 7.5 (.46 – 4.68)

FREE T4 0.82 (0.80-1.50). TPO-Ab 317 reactive greater than 40

Case 2 continued

• DX: Subclinical Hypothyroidism• Hashimotos thyroiditis

• Tx: “Brand LT4” 25 mcg q.d. Follow-up and TSH in 2 months.• Follow-up: patient feeling better

without complaints TSH 1.89 (0.5 – 3.0) Education, need to follow

Non specific symptoms Osteoporosis Anemia Heart Failure Treatment with thyroxine Start with small doses and titrate

slowly. (25ug).

Elderly

Incidence is about 9%. Transitory or permanent. Early hyperthyroidism (<4/12), later

hypothyroidism (>4/12), euthyroid 10/12 later.

Increased microsomal antibodies. Thyroxine

Post-partum thyroiditis.

Requires prompt treatment. Mortality of 50%.

Suspect in cases of hypothermia. T3 20ug bd IM Steroids recommended Glucose to correct hypoglycaemia Rewarming Assisted ventilation

Myxoedema Coma

Hyperthyroidism

HYPERTHYROIDISMETIOLOGY

• Graves’ disease ( autoimmune ).• Toxic multi-nodular goiter ( toxic MNG ).• Toxic nodule (hot or warm nodule)

Common Symptoms and Signs of Thyrotoxicosis

Symptoms

• Nervous / shaky

• Fatigue• Muscle weakness• Increased perspiration

• Heat intolerance• Tremor• Palpitations• Appetite/weight changes Menstrual disturbances

Signs

• Goiter • Hyperactivity • Tachycardia /

arrhythmia • Systolic hypertension• Warm, moist, or smooth

skin• Stare and eyelid

retraction• Tremor • Hyper-reflexia

GRAVES’ Dz

• ~75% of cases of hyperthyroidism.• Thyroid Stimulating Immunoglobulins (TSI’s)

and / or TSH receptor antibodies (TRAb) levels usually increased

• Incidence 2nd – 4th decade of life.• ~5 times more likely in women.

Thyrotoxicosis - work-up

• Labs- demonstrate thyrotoxicosis.– TSH - Low or undetectable – Free T4 and/or Free T3 – Increased

I123 thyroid scan / uptake• Uptake is increased.

– 4 hour: normal ref. (5 – 15%)– 24 hour: normal ref. (6 - 30%)

• Scan (anatomical findings via radiotracer uptake)– Homogeneous ( Graves’ Dz)– multiple areas (Toxic MNG)– single area (Hot or warm nodule)

PATIENT EXAMPLEGRAVES’

• 30 y.o. female with nervousness, shakiness, heat intolerance, “fast / pounding heart beat”, wt loss, light menses, and muscle weakness for 3 months.

• P.E. HR=118– Eyes—lid lag, stare,

– Skin: warm/moist– Thyroid: large symmetric non-

tender gland– Neuro—tremors, DTR’s – brisk,

hyper-reflexic • LABS: TSH: < 0.03 (0.45 – 4.50)

FT4: 2.8 (0.8-1.8)

Graves’ Work up Cont.

• I123 thyroid S/U 4hr = 28% (5 - 15%) 24hr = 76% (6 - 30%) diffuse homogeneous uptake.

TREATMENT options

Treatment of Hyperthyroidism

Treatment depends upon -Cause and severity of disease -Patients age -Goiter size -Comorbid condition -Treatment desired

Treatment

The goal of therapy is to correct hyper-metabaolic

state with fewest side effects and lowest incidence of hypothyroidism.

Options Anti-thyroid drugs Radioactive iodine Surgery Beta-blocker and iodides are adjuncts to above

treatment

Beta Blockers

Prompt relief of adrenergic symptoms Propranolol widely used Any beta blocker can be used, but non-

selectives have more direct effect on hyper-metabolism

Start with 10-20 mg q6h Increase progressively until symptoms are

controlled Most cases 80-320 mg qd is sufficient CCB can be used if beta blocker not tolerated

or contraindicated

Iodides

Iodide blocks peripheral conversion of T4 to T3 and inhibits hormone release. These are used as adjunct therapy

• Before emergency non-thyroid surgery• Beta blockers cannot curtail symptoms• Decrease vascularity before surgery for

Grave’s disease

Iodides

Iodides are not used for routine treatment because of paradoxical increase of hormone release with prolonged use

Commonly used: Radiograph contrast agents -Iopanoic acid -Ipodate sodium Potassium iodide Dose 1 gram/ 12 weeks

Anti-thyroid Drugs

They interfere with organification of iodine—suppress thyroid hormone levels

Two agents: -Tapazole (methimazole) -PTU (propylthiauracil)

Anti-thyroid Drugs

Remission rate: 60% when therapy continued for two years

Relapse in 50% of cases. Relapse more common in -smokers -elevated TS antibodies at end of therapy

Anti-thyroid Drugs

Methimazole

Drug of choice for non-pregnant patients because of :

Low cost Long half life Lower incidence of side effects Can be given in conjunction with beta-blocker Beta-blockers can be tapered off after 4-8

weeks of therapyDose 15-30 mg/day

Anti-thyroid Drugs

Methimazole Monthly Free T4 or T3 until euthyroid Maintenance dose 5-10 mg/day TSH levels may remain undetectable for months

after euthyroid and not to be used to monitor the therapy

Anti-thyroid Drugs

Methimazole At one year if patient is clinically and

biochemically euthyroid and TS antibodies are not detectable, therapy can be discontinued

Monitor every three months for first year then annually

Relapses are more common in the first year but can occur years later

If relapse occurs, iodide or surgery although anti-thyroid drugs can be restarted

Anti-thyroid Drugs

PTU Prefered for pregnant patients Methimazole is associated with rare genetic

abnormalities Dose 100 mg t.i.d Maintenance 100-200 mg/day Goal: Keep Free T4 at upper level of normal

Anti-thyroid Drugs

Complications Agranulocytosis up to 0.5% High with PTU Can occur suddenly Mostly reversible with supportive Tx Routine WBC monitoring controversial Some people monitor WBC every two weeks

for first month then monthly Advised to stop drug if they develop sudden

fever or sore throat

Treatment with 1131 RAI

• Treatment of choice– Goal is complete ablation i.e. hypothyroid– Hypothyroid about 3-5 months post I131 Tx

• Follow Free T4 q 4-6 weeks until low– Treatment: “brand” LT4– Follow and treat as you would for hypothyroid– Exception: the low TSH usually lags behind,

often for months, the normalization of the Free T4.

– Check Free T4 and TSH until the TSH becomes normal or high, then only follow the TSH.

Thyroid Nodules

How thyroid nodules or masses are found?

• By HCP: palpation on routine exam• By patient: rarely• Incidentally

– CT scan or MRI of chest / neck – Carotid Dopplers

• Thyroid Ultrasound• I123 thyroid scan / uptake

Thyroid Nodules

• 5 categories: – Benign– Non-diagnostic– Follicular neoplasm/lesion– Suspicious– Malignant.

• Size - >1cm “dominant nodule”

Thyroid Nodules

• I123 thyroid scan / uptake – Hot or warm – hormone secreting

nodules– Cold nodules can be:

• Cysts• Benign adenomas• Malignant tumors• others

Ultrasound findings that increase the risk of malignancy

• Hypoechoic• Microcalcifications• Irregular margins• Intranodular vascularity• Rounded appearance; more tall than

wide, shape of the nodule

Suspicious for malignancy

• Growing nodule• Fixed nodule• Firm or hard consistency• Cervical adenopathy• History of head and neck irradiation• Family history of medullary thyroid carcinoma

(MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC)

• Persistent dysphonia, dysphagia or dyspnea• Age <30 or >60 years• Male sex

Thyroid Nodule Work-up

• Assess for biochemical abnormality. (TSH, FT4, ?FT3)

• If normal Labs – U/S to evaluate: number and echotexture.– Cytopathological Eval. Fine needle aspiration (FNA)

with or without U/S guidance.• If abnormal Labs:

low TSH and or increased FT4/FT3 – I123 thyroid scan and uptake– Nodule(s) hot or warm– Treat options: I131 RAI, ATD’s, Surgery, refer to

endocrinologist for treatment

Cold Nodules on I123 Thyroid scan/uptake

• TSH and Free T4 normal– Consider thyroid cancer, benign adenoma,

or thyroid cyst– Ultrasound to delineate solid vs. cystic

lesion– Referral for ultrasound guided FNA biopsy– If biopsy is suspicious for cancer or

demonstrates cancer, referral to surgeon with ample experience in thyroid surgery.

Thyroid Malignancies

• Papillary: ~80%• Follicular: ~15%• Medullary: ~3-5%• Anaplastic: < 2%