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Ronnie B. Martin, D.O., FACOFP-dist

Professor of Family Medicine

Dean, Liberty University College of Osteopathic Medicine

Thyroid Physiology T3 and T4 are transported in the serum reversibly

bound to proteins; principally thyroxine-binding globulin (TBG) and to a lesser extent albumin.

Only free T4 and free T3 are metabolically active.

In the serum, 0.04% of total T4 and 0.4% of T3 are in free or active forms ( 10-x as much T3 as T4)

Peripheral metabolism converts T4 to more active T3 through de-iodination.

T3 has has up to 10 times the potency of T4.

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Hypothyroidism More common in women (up to 8:1)

Occurs 2-3% of general population

~ 6% of female patients > 60 and increases with age up to ~15% of women > 80 years old

Most common cause world wide:

Iodine deficiency

Most common in US:

Chronic Autoimmune Thyroiditis or Hashimoto’s Thyroiditis

Hypothyroidism Pathophysiology:

Primary Hypothyroidism: Thyroid gland failure to respond to Thyroid Stimulating Hormone (TSH) due to either blockage at receptor site or thyroid tissue cellular destruction

Self-limiting causes include post partum thyroiditis and painless thyroiditis

Can be secondary to drugs: i.e. lithium (which blocks release), amiodarone or excessive iodine

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Hypothyroidism Pathophysiology:

Secondary Hypothyroidism: Deficient TSH production secondary to anterior pituitary

dysfunction or failure to respond to Thyrotropin-releasing hormone (TRH) from the anterior pituitary. More rarely, an abnormal TSH is produced that will not stimulate

production of T4 and T3

Dopamine and lithium known to produce secondary hypothyroidism

Tertiary Hypothyroidism: Lack of TRH Production from hypothalamus secondary to metabolic or

structural defects.

Hypothyroidism: Clinical Signs and Symptoms:

Fatigue and weakness Cold intolerance Dyspnea on exertion Weight gain Cognitive dysfunction Mental retardation

(infant) Constipation Decreased GI motility Decreased sweating Angina

Growth failure Slow movement Slow speech Delayed relaxation of

tendon reflexes (slow DTR’s)

Carpal Tunnel Syndrome

Bradycardia and decreased contractility

Pleural and pericardial effusions

Diastolic hypertension

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Hypothyroidism: Clinical Signs and Symptoms:Dry, thick, discolored Skin

Course Hair

Hair Loss-esp. lateral eyebrows

Hoarseness

Pretibial non pitting edema

Puffy faces

Periorbital edema

Macroglossia (children)

Depression

Abnormal Menses(heavy)

Infertility

Arthralgia

Myalgia and paresthesia

Pubertal delay

Decreased hearing

Ascites (rare)

Galactorrhea

Hypothyroidism: Laboratory Evaluations Primary Hypothyroidism (95% of all cases)

Overt Hypothyroidism Elevated TSH (> 5mU/L) and low FT4

Subclinical Hypothyroidism Elevated TSH and normal FT4

Up to 5% of all patients and up to 20% of all female patients have presence of thyroid antibodies: either thyroid peroxidase antibodies (TSO) and/or thyroid globulin antibidies (Tg) present even in absence of clinical signs of thyroiditis or hypothyroidism.

Secondary or Tertiary Hypothyroidism (5%) Low or normal TSH and low FT4

Normal or low TRH

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Treatment of Hypothyroidism: Primary hypothyroidism treatment consists of thyroid

hormone replacement

Drug of choice is synthetic thyroxine (T4)

Thyroxine is deioninated in peripheral tissues to active agent, T3 (triiodothyronine)

Once daily dose due to long (6-7 day) ½ life

Allows consistent serum T4 and T3 levels

80% absorbed from GI

Should be taken on empty stomach, high fat meals reduce absorption up to 40%.

Treatment of Hypothyroidism: Dosage calculated on lean body weight, not total body

weight

Serum levels higher if given at night vs. AM (timing related to meal and empty stomach)

Average dosage 1.6mcg/kg/day (112mcg in 70 kg adult)

T4 levels peak within 2-3 weeks

TSH may not fall to steady state for up to 6 weeks (requiring 6- ½ lives- to stabilize)

Weekly dosage administration has been utilized in patients without CAD with good clinical results

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Treatment of Hypothyroidism: Patients with cardiac conditions should be started

with not greater than 25mcg/day and titrated every 3 to 6 weeks in 25mcg increments

Thyroid hormones increase cardiac oxygen demand and may result in angina or arrhythmias

Elderly patients (>50-60 depending on co-existent disease) should start with 50mcg/day and titrate q. 3 to 6 weeks

Some neuromuscular and psychiatric symptoms may not disappear for several months

Treatment of Hypothyroidism: Initial dosage for infant to prevent cretinism and risk

of mental retardation, etc. is 10-15mcg/kg/day and should be started immediately via I.V.

Dosage for treatment of patient after thyroid cancer surgery or I-131 treatment uses higher with goal to reduce TSH to <0.01 mU/L to suppress carcinoma in any remaining tissue.

Surgical patients do not need parental replacement unless they are to remain NPO >5 to 7 days if on T4 products

If given IV, dosage is 80% of oral

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Treatment of Hypothyroidism: In Pregnant women that are known to be hypothyroid prior to PG, dosage of

T4 should be increased 30% as soon as PG is confirmed and TSH followed each trimester. Demand often increases as much as 45% by end of second trimester

Euthyroid PG patients generally adjust on own and do not need Rx Euthyroid patients or subclinical hypothyroid patients with the

presence of thyroid peroxidase antibodies may also require T4 therapy during PG

Women on T4 therapy who initiate estrogen replacement therapy should have TSH checked in 12 weeks and may require increased dosage Changes in TSH and T4 are not noted in euthryoid women who initiate E2 therapy

Treatment of Hypothyroidism: Dosage Adjustments required: Patients with impaired acid secretion or other GI

disorders that interfere with absorption

Nephrotic syndrome accelerates excretion and requires higher dosage.

High fat or high fiber diets inhibit absorption

Coffee instead of water reduces absorption by 27-36%

Medications such as rifampin, carbamazepine, phenytoin, sucralfate, Phenobarbital, ciprofloxin, iron salts, antacids etc alter levels of drug due to competitive metabolism in liver primarily.

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Treatment of Hypothyroidism: Triiodothyronine (T3) preparations are available as

well as desiccated thyroid and mixtures of T3 and T4 but are not recommended for primary treatment:

Variation in potency and bioavailability of desiccated thyroid provide inconsistent hormone levels

Short ½ life (~ 12 hours) and variable GI absorption of T3 leading to fluctuations in serum T3 concentrations

Secondary and Tertiary Hypothyroidism: Primary treatment is administration of T4

Must keep in mind other hormonal deficiencies, cortisol, growth hormone in children, sex hormones, etc. may be present as well due to pituitary or hypothalamic defects.

Addition of T4 to patient with adrenal insufficiently will ppt. acute adrenal crisis if not accompanied by glucocorticoid

Cortrosyn stimulation test generally done before T4 stared in these conditions

Monitoring of therapy in secondary and tertiary cases generally requires monitoring of T4 levels, not TSH (TSH values not responsive to serum levels)

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Subclinical Hypothyroidism Elevated TSH and normal serum free T4 and T3 levels

Subclinical hypothyroidism in presence of PG generally indication for treatment

If anti-thyroid peroxidase antibodies (TSO) present, conversion to overt hypothyroidism occurs in 5-8% per year and treatment with T4 agents considered

If goiter present in face of normal T4, treatment may be indicated for elevated TSH

If TSH elevated > 10 mU/L, recommend initiation of treatment

Myxedema Coma Mortality rate approaches 80%

Draw blood for T4, TSH and cortisol but do not wait for results to initiate therapy

Administer I.V. glucocorticoid and thyroid

Correct hyponatremia, fluid defects, hypothermia, assist respirations, treat underlying cause, infection, etc.

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Etiology and Pathogenesis of Hypothyroidism1. Hashimoto’s thyroiditis

Autoimmune destruction of thyroid

Goiter present early and resolves

Mild to severe hypothyroidism

2. Drug induced hypothyroidism

Blocked hormone formation from agents such as iodides, lithium, flouride, thioamides, aminosalicylicacid, phenylbutazone, amiodarone, etc

Goiter present

Mild to moderate hypothyroidism produced.

Etiology and Pathogenesis of Hypothyroidism3. Dyshormonogenesis

Impaired synthesis of T4 due to enzyme deficiency

Goiter present early and persistent

Mild to severe hypothyroidism

4. Radiation induced (I-131, X-ray, thyroidectomy)

Destruction or removal of glad

Absent goiter

Severe hypothyroidism

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Etiology and Pathogenesis of Hypothyroidism5. Congenital (cretinism)

Athyreosis or ectopic thyroid, iodine deficiency, TSH receptor blocking antibodies

Goiter generally absent at birth

Severe hypothyroidism

6. Secondary (TSH defect)

Pituitary or hypothalamic disease

Absent goiter

Mild to moderate hypothyroidism

Hashimoto’s Thyroiditis: Chronic Autoimmune thyroiditis Most common cause of hypothyroidism in the iodine

sufficient areas of the world

Two forms: goitrous and atrophic

Differ in degree of lymphocytic infiltration, fibrosis and thyroid follicular cell hyperplasia but pathophysiology identical

Clinical characteristics:

Gradual thyroid failure

Multinodular goiter formation noted with time.

Rarely painful vs. thyroiditis

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Precipitating Factors: Hashimoto’s Thyroiditis Genetic susceptibility

Clusters in families with sibling recurrence risk >20 % Seen in 30-60% of monozygotic twins Increased incidence with Down’s and Turner’s syndromes Increased incidence in patients with history of other

autoimmune diseases such as insulin deficient diabetes or adrenal insufficiency

Triggers: Infection

No specific virus identified

Metabolic stress Secondary to effects of cortisol or corticotropin-releasing hormone

on immune cells

Precipitating Factors: Hashimoto’s Thyroiditis Sex steroids and Pregnancy increase occurrence of

Hashimoto’s

Correlation between smoking and thyroid disease esp. in women with autoimmune thyroid disease

Iodine intake

Mild deficiency has lower prevalence and excessive intake is associated with higher prevalence

Ionizing radiation

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Hashimoto’s Thyroiditis Pathophysiology: Autoimmune mediated destruction of

the thyroid gland with apoptosis of thyroid epithelial cells.

Intense lymphocytic infiltration predominantly with thyroid specific B and T cells B cells secret thyroid antibodies

T cells secret cytokines and accelerate cytotoxicity as well as produce antibodies and stimulate B cells to produce antibodies

Results in follicular destruction Fibrosis and follicular cell hyperplasia

Destruction of thyroid follcies

Hashimoto’s Thyroiditis

Patients have high serum concentrations of polyclonal antibodies directed against thyroid antigens and antigen specific T-cells:

Thyroid peroxidase (TPO)

Thyroglobulin (Tg)

TSH receptor blocker antibody

These antibodies can fix complement as well as direct cytolysis which adds to the cytotoxicity and thyroid destruction 11-18% of women who are euthyroid demonstrate these antibodies

TSH antibodies present in Hashimoto’s patients block the action of TSH rather than activate it as found in Graves’ disease. Stimulating TSH receptor antibodies are specific for Graves disease

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Hashimoto’s Thyroiditis Predominately a disease of females with ratio of 7:1

Most common cause of hypothyroidism in children, occurring as early as 1 year of age

Inflammatory process early in disease can cause transient hyperthyroidism

Rare patient may cycle between hypothyroidism and Graves’ disease due to alternative production of thyrotropin (TSH) receptor blocking and stimulating antibodies

Hashimoto’s Thyroiditis TSH generally elevated

FT4 low

T3 low

TPO (antithyroid peroxidase) antibodies present in 90-95% of patients

Tg (antithyroglobulin) antibodies present in 70-75%% of patients

TSH receptor blocking antibodies less reliable but found in 20-25% of patients

Ultrasound generally show hypoechogenic appearance

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Treatment:Hashimoto’s Thyroiditis Hypothyroid patients—levothyroxine

Hyperthyroid patients-transient use of thionamidesand BB

Euthyroid patients with goitrous thyroiditis

Levothyroxine treatment will produce up to 30% reduction in size for up to 90% of patients in 6 to 18 months

Radioiodine-very rare

30-60% reduction in size

Thyroidectomy-even more rarely indicated

Hashimoto’s Encephalopathy Immune mediated antibody directed neuronal injury

disorder not directly due to altered hypothyroid state

Marked by confusion, altered level of consciousness, seizures and myoclonus

Responds to high dose steroid therapy (98%) although patients have been treated with other immunosuppressive medications (azathioprine and cyclophosphamide)

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Hyperthyroidism: Hyperthyroidism more common in women that men

(7:1)

Overall incidence 1% of population, increases to 5% in older women

Graves Disease most common cause and seen most frequently in women (5:1) in ages 20-40

Toxic multinodular goiter (Plummer’s disease) more common older women as a cause of hyperthyroidism

Hyperthyroidism: Factors associated with Graves’ disease:

Cigarette smoking (esp. related to graves ophthalomopathy) Genetic link

Disease clusters in families with sibling recurrence rate >10.0 and concordance rate in monozygotic twins 20-40%

Psychological stress (depressed immune system function mediated by cortisol)

Thyroid injury Infection

Yersinia enterocolitica Radiation Drugs

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Hyperthyroidism: Factors associated with Graves’ disease:

Sex steroids

PG --decreased incidence during PG but up to 30% of young women with Graves’ give history of PG in 12 months before onset of disease

Iodine—allows TSHR-Ab to stimulate more production and release

Hyperthyroidism: Autoimmune thyroid disease or autonomous thyroid tissue

Graves disease: -the result of autoimmune produced thyrotropinreceptor simulation antibodies(TSHR-Ab) actions on the gland

Hashitoxicosis-autoimmune disease with initial presentation as hyperthyroid before deteriorating to hypothyroid state (both TSH receptor blocker and TSH receptor stimulation genes/Ab present)

Toxic adenoma and toxic multi-nodular goiter -result of focal or diffuse hyperplasia of thyroid follicular cells independent of regulation by TSH (possible due to mutations of TSH-receptor gene)

Toxic multinodular goiter most common in areas where iodine intake is low

Adenoma occurrence not related to iodine intake

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Hyperthyroidism: Increased synthesis

Trophoblastic disease and germ cell tumors-(Directly stimulate TSH receptor) Women-hydatidiform mole or choriocarcinoma

Men-testicular germ cell tumor

TSH Mediated hyperthyroidism Pituitary adenomas

Resistance to feedback effect of thyroid hormone on TSH production

Mutation in nuclear triiodothyronine (T3) receptor

Mutation of TSH receptor itself

Iodine induced hyperthyroidism Uncommon, seen post iodine load such as contrast agent or food

supplement

Hyperthyroidism: Thyroiditis Inflammation and destruction of thyroid yielding release of

performed hormone into circulation Sub acute granulomatous thyroiditis (de Quervain’s

thyroiditis) Viral or post viral infection accompanied by fever, malaise,

painful and tender goiter Silent or painless thyroiditis- an autoimmune disease with tendency

to occur in post partum period (postpartum thyroiditis) Direct chemical toxicity with inflammation Radiation thyroiditis Drugs that interfere with immune system (interferon alfa,

cyclosporin etc) Beta blockers, anti-inflammatory agents first line treatment Ipodate useful to block conversion of T4 to T3 in periphery and reduces

tissue effects of Thyroid hormone Thionamides have no role in treatment of thyroiditis as no abnormal

amounts of hormone are being synthesized

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Clinical Manifestations of Hyperthyroidism: Decreased bone density Elevated biochemical markers of

bone resorption: increased osteocalcin increased urinary

hydroxyproline

Increased serum glucose Increased serum Ca and Alk

Phos. Decreased LDL and Cholesterol Increased hepatic enzymes and

creatine kinase Increased sex hormone binding

globulin (altered menses and fertility)

Increased Heart Rate Presence of atrial fibrillation Increased cardiac contractility Increased LV mass index Exophthalmos or specific

opthalmopathy Large, tender thyroid Restless and irritability Weight loss Finger tremor Increased sweating

Graves’ Disease Autoimmune Disease caused by auto antibodies to

thyrotropin (TSH) receptor (TSHR-AB) which activates the receptor and results in increased thyroid hormone synthesis, secretion (release) and growth of thyroid gland

The presence of TSHR-Ab in serum and ophthalmopathy on clinical exam distinguishes from other causes of hyperthyroidism and diffuse goiter.

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Graves’ Disease Most common cause of hyperthyroidism in US

Syndrome of hyperthyroidism, goiter, ophthalmopathy(orbitopathy) and pretibial or localized myxedema

Hyperthyroidism is most common feature

Immune pathogenesis of Graves disease: TSHR-Ab B and T cells both active in the production of TSHR-

Ab responsible for production of thyroid hormone, thyroid stimulation and growth, primarily in the thyroid gland itself.

Specific for Graves’ disease

Unique to humans

Usually IgG1 oligoclonal antibodies

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Graves DiseaseGraves’ disease may develop over a background of

thyroiditis as evidenced by the presence of lymphocytic infiltration of the gland, anti-Tg, anti-TSO antibodies and TSHR-Ab in both Graves and Hashimoto’s thyroiditis

Laboratory Findings in Graves’ Disease Elevated T4 and T3

Elevated Free T4 and T3

Serum THS depressed (often < 0.1 units/ml)

Positive anti-TSH receptor antibody (TSHR-Ab)

Often Tg and TPO antibodies as well

Elevated I-123 or Tc-99 uptake

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Treatment of Hyperthyroidism and Graves’ Disease: Determine etiology of elevated T4

Treat hyperthyroid symptoms with beta blocker

Propranolol is only BB that inhibits peripheral conversion of T4 to T3 and has better penetration into CNS to control symptoms there as well.

In thyroid storm, utilization of Iodine (KI) and adrenal corticosteroids in addition to anti-thyroid drugs and BB

Treatment of Hyperthyroidism and Graves’ Disease: Three means to decrease thyroid synthesis, each

equally effective within 6 weeks

Administration of a thionamide

Radioactive ablation with I-131

Surgery

Rate of relapse 37%, 21% and 6% respectively

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Special Consideration in Graves Disease: Ophthalmopathy and Dermopathy

Exopthalmus: In addition to management of thyroid disease a tapering dose of steroids over 6 to 12 weeks is generally required.

Eye surgery is often indicated if dipolpia or loss of vision is threatened.

Dermopathy:

Utilization of oral or topical corticosteroids are indicated for treatment

Toxic Single-nodular Goiter and Toxic Multinodular Goiter Often associated in elderly women with nodular

goiters

Single toxic adenoma are treated with surgical excision or radioiodine therapy.

Multinodular goiter is usually treated initially with the thionamide methimazole followed by subtotal thyroidectomy

Marked by only mild elevation in T4 but marked elevation in T3.

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Sub-acute Thyroiditis: Marked by swollen, painful thyroid gland seen during

the acute phase of a viral infection of the thyroid gland.

Fever, sore throat, voice changes, tremor, tachycardia and other sympathomimetic changes are hallmarks.

Treated symptomatically with B.B., analgesics, occasionally corticosteroids.

Thionamides: Inhibit production of thyroid hormones (organification of

iodine to tyrosine and coupling of iodotyrosines to form T3 and T4) May also inhibit thyroid hormone secretion

May have immunomodulatory activity on autoimmune disease

High dose vs. low dose treatment (30-40mg/day vs. 10-15 mg/day) No difference in remission rates

Initial response faster to high dose, more side effects and complications

Principle side effects Rash, nausea, hepatitis, vascultitis, agranulocytosis-all more

common with PTU

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Thionamides: Methimazole

Preferred due to less side effects and toxicity, longer duration of action, more rapid efficacy

Starting dose generally 10-15 mg daily

With larger goiters and more severe symptoms, dosage of 20-30 mg/day can be used initially (divided doses)

Maintenance dosage generally 5-15 mg daily

Duration of therapy generally 12 to 18 months, but has been used for up to 10 years safely

Permanent remission after cessation of therapy in only 20-30% of patients

Thionamides: Propylthiouracil (PTU)

Drug of choice in PG patients due to teratogeniceffects of methimazole

Dosage 300-450mg daily initially in 2 to 3 doses

Maintenance dose is 50-300 mg in 2 to 3 doses

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Alternative Therapies: Iodinated contrast agents and iodine

Na Ipodate and Na Iopanoic acid are inhibitors of conversion of T4 to T3 and are used in combination with methimazole

SSKI long time treatment for low grade hyperthyroidism at 10 drops daily.

Cholestyramine Dose of 4g four times daily with methimazole`

Glucocorticoids-esp. for exophthalmos but also inhibit peripheral conversion of T4 to T3 and reduce thyroid secretion.

Radioiodine Ablation and Surgery Therapy of choice in US (69%)

Used only 22% in Europe and 11% Japan

I-131 as capsule or oral solution

Patients who are elderly or have heart disease are usually pretreated with thionamide initially

Ablation requires 6 to 18 weeks for euthyroid state--20% will need second round of treatment

Surgery indicated primarily for patients with obstructive goiter, in pregnant women allergic to Rx or those refusing radiation therapy.

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Monitoring of Hyperthyroidism Treatment: Must monitor free T4 and T3 as TSH will be late to

respond, remaining low for weeks before rebounding

Those with T3 dominate Graves’ disease respond less well to thionamide therapy

Remission more likely in women < 40 vs. >40.

Those with low TSH more than 6 months after starting Rx not likely to achieve remission after cessation of Rx

Patients with TSH receptor antibody negative status before or after therapy have higher remission rate (77%)

Rare, potentially fatal condition that may result from untreated or partially treated thyrotoxicosis

Must be recognized and treated on clinical basis, not waiting on lab testing

PRECIPITATING EVENTS

SURGERY

INFECTION

TRAUMA

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Thyroid Storm:Early Hypermetabolic Changes

Progressive Deterioration

HIGH FEVER

TACHYCARDIA

NAUSEA

VOMITING

TREMULOUSNESS

AGITATION

PSYCHOSIS

STUPOROUS

COMATOSE

HYPOTENSION

DEATH WITH TREATMENT 10-20%

UNTREATED DEATH 100%

Treatment of Thyroid StormCARDIAC MONITORINTUBATION IF NEEDSUPPLEMENTAL OXYGENCOOLING MEASURESAGGRESSIVE HYDRATION

REPLACE ELECTROLYTESINTRAVENOUS

GLUCOCORTICOIDSANTITHYROID MEDS

PTU, METHIMAZOLE Can be given orally or rectally

IODIDE, (SSKI or Na Ipodate 1 gm) One hour after loading dose of anti-thyroid medication

BETA-ADRENERGIC BLOCK Propranol or if contraindicated the

Calcium Channel Blocker Diltiazem 90-120 mg orally