Hypothyroidism

Kommerien Daling, MD Chiefs Conference August 14th 2008

Overview
Definitions Epidemiology Physiology Symptomatology Causes of hypothyroidism Evaluation & treatment Screening

Definitions
Goiter: enlarged thyroid gland, diffuse or nodular. toxic, non-toxic or under-active. Hypothyroidism: deficiency of thyroid hormone. primary, secondary or tertiary Subclinical hypothyroidism: TSH concentration above the statistically defined upper limit of the reference range when serum free T4 [thyroxine] concentration is within its reference range

Epidemiology
Overt hypothyroidism prevalence 0.1-2% Prevalence in HLD 4.2% Subclinical hypothyroidism prevalence 4- 8.5%, 20% in women > 60 Goiter 16% in a UK study Nodules in 50% on autopsies, in 40% with high resolution ultrasound

Epidemiology
95 % is primary hypothyroidism Hashimotos thyroiditis most common cause of hypothyroidism and goiter in noniodine deficient regions, USA Appalachia: Hashimotos prevalence 6% Worldwide: 2 billion people I deficient US urinary iodine excretion 168mcg/L in 2002, 320mcg/L in 1971. 7% of pregnant women in 2002 vs 1% in 1971 with urinary iodine < 50mcg/l

Thyroid hormone biosynthesis

Thyroid hormone synthesis includes the following steps: (1) iodide (I -) trapping by the thyroid follicular cells; (2) diffusion of iodide to the apex of the cells; (3) transport of iodide into the colloid; (4) oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues within thyroglobulin molecules in the colloid; (5) combination of two diiodotyrosine (DIT) molecules to form tetraiodothyronine (thyroxine, T4) or of monoiodotyrosine (MIT) with DIT to form triiodothyronine (T3); (6) uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4, T3, DIT, and MIT; (7) release of T4 and T3 into the circulation; and (8) deiodination of DIT and MIT to yield tyrosine. T3 is also formed from monodeiodination of T4 in the thyroid and in peripheral tissues. Modified from Scientific American Medicine, Scientific American, New York, 1995.

TSH activity
Increases iodide uptake and transport Stimulates iodination/organification Stimulates T4 and T3 synthesis Increases thyroglobulin levels, TPO, lysosomal activity, T3/4 secretion Stimulates membrane phospholipase C thyroid cell hypertrophy goiter dopamine, dobutamine, octreotide & stress decrease TSH secretion glucocorticoids decrease TRH secretion

Serum binding proteins

TBG, TTR (transthyretin), albumin, LP Act as storage and buffer, help maintain free hormone within narrow limits, immediate bioavailability T4 99.97% bound, TBG 75%, TTR 10%, Albumin 12%, lipoprotein 3% T3 99.5% bound, TBG 80%, TTR 5%

T4 to T3
Free T3 is 3-5 times more active than free T4 80% of T3 is formed by deiodination of T4 in peripheral tissues Deiodinase type 1 in liver, kidney, thyroid Deiodinase type 2 in brain, muscle, pituitary & placenta (type 2 not PTU sensitive) Deiodinase activity uio nutritional, hormonal & illness related factors Deiodinase type 3: T4 rT3 (elevated in NTIS)

Pathways of thyroid hormone metabolism

Thyrotropin-releasing hormone (TRH) increases the secretion of thyrotropin (TSH), which stimulates the synthesis and secretion of trioiodothyronine (T3) and thyroxine (T4) by the thyroid gland. T3 and T4 inhibit the secretion of TSH, both directly and indirectly by suppressing the release of TRH. T4 is converted to T3 in the liver and many other tissues by the action of T4 monodeiodinases. Some T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine. Some T4 and T3 formed in the intestine may be reabsorbed. Drug interactions may occur at any of these sites.

Major symptoms and signs of hypothyroidism

Mechanism Symptoms Signs Fatigue and weakness Cold intolerance Dyspnea on exertion Weight gain Cognitive dysfunction Mental retardation (infant) Constipation Growth failure

Slowing of metabolic processes

Slow movement and slow speech Delayed relaxation of tendon reflexes Bradycardia Carotenemia

Accumulation of matrix substances

Dry skin Hoarseness Edema Nerve entrapment

Coarse skin Puffy facies and loss of eyebrows Periorbital edema Enlargement of the tongue

Other

Decreased hearing Myalgia and paresthesia Depression Menorrhagia Arthralgia Pubertal delay infertility

Diastolic hypertension Hair loss Pleural and pericardial effusions Ascites Galactorrhea Ataxia

Diagnosis of hypothyroidism
Diagnosis based on labs. Symptoms nonspecific Indications to test: signs or symptoms goiter presence of other lab abnormalities (eg Na, lipids, anemia, CK, chol, prolactin) Presence of hypothalamic or pituitary d/o Post partum status

Diagnostic evaluation
TSH excellent 1st test (95% is primary dz) Repeat if abnormal, with fT4 Distinguish between primary and central (2ndary, 3tiary) Then distinguish between overt, subclinical

DDx of elevated TSH

Primary hypothyroidism Transient Recovery from NTIS Pituitary adenoma Primary adrenal insufficiency T4 resistance TSH resistance at receptor level

fT4 low, TSH low

Central hypothyroidism Imaging indicated to distinguish hypothalamic from pituitary disease Evaluate for 2dary adrenal insufficiency

Algorithm subclinical hypothyroidism

USPSTF recommendation for Screening

The USPSTF concludes the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults. Yield of screening is greater in high-risk groups (e.g., postpartum women, people with Down syndrome, and the elderly), the USPSTF found poor evidence that screening these groups leads to clinically important benefits There is good evidence that over-treatment with levothyroxine occurs in a substantial proportion of patients, but the long-term harmful effects of over-treatment are not known

Screening
The 2002 consensus group's expert panel recommended against population-based screening but "encouraged" assessment in high-risk groups: Women > 60 women with a family history of thyroid disease, prior thyroid dysfunction, symptoms suggestive of hyperthyroidism or hypothyroidism, abnormal thyroid gland on examination, type 1 diabetes personal history of autoimmune disorder
Consensus group consisted of members of the ATA, AACE, & ES

AAFP recommendation for Screening

it is common practice to screen patients with dyslipidemia for hypothyroidism

Cost analysis 5 yr-ly screening

F @ 35yo: $9,000/QALY (4000/2000) F @ 60yo: $5,000/QALY (2000/cost saving) M: cost x 2.5 breast cancer screening: $5,000/QALY HTN screening: $22,000/QALY Medicare does not pay for screening: use symptom

Screening in the very elderly?

>85 yo: TSH associated with survival evidence for benefit of not treating requires RCT

Other tests
fT3 not very useful: often wnl even in severe hypothyroidism T3 may be low in 70% of hospital patients rT3 to support dx of NTIS THBI, T3 resin uptake (T7), free T4 index Ultrasound (leading to incidentalomas)

Nodule & incidentaloma algorithm

Normal TSH

Thyroid nodule

TSH (& anti TPO)

REFER to endocrinologist for cost saving

Decreased TSH

High TSH &/or anti-TPO Hashimotos

Tx w/ T4

FNA
undiagnostic Malignant 5% Indeterminate 10% Benign 70%

Uptake scan

hot

observe
observation

Scintigraphy may show nodule as 1 functioning lobe -> Biopsy not indicated

surgery

Uptake scan

ultrasound
Infiltrate vs hyperplasia vs tumor vs cyst. Rapid shrinkage >50% with T4 tx is reassuring, but not R/O malignancy

cold

indeterminate

hot

Suppression scan

Causes of hypothyroidism
Chronic AI thyroiditis Hashimotos Transient: painless, post partum, subacute thyroiditis Iatrogenic: injury, medication induced Defenciency or excess iodine Infectious thyroiditis Infiltrative disease Central hypothyroidism GRTH generalized resistance to thyroid hormone

Risk Factors for thyroiditis

age female goiter prior thyroiditis H/O AI-dz, FH of AI Downs, Turners, primary PHTN, MS,

excess iodine intake previous injury: (XRT, surgery, chemical exposure PCBs, resorcinol vigorous physical exam)

Hashimotos disease
Goitrous (more common) or atrophic Humoral and cellular inflammatory proces In 90% elevated, TPO> TGB> TSHR, Na/I transporter antibodies Cytotoxic T cells high incidence in elderly women ? estrogen deficiency

Hashimotos disease ctd

Assoc w/ high I intake: anti thyroid antibodies smoking assoc w/ onset of hypothyroidism in pre-existent Hashimotos Course: slow onset (months to years), usually permanent, remissions occur usually presents with non specific sx or goiter, rarely with myxedematous coma, precipitated by stress/infection

Hashimotos disease ctd

Antibodies can confirm clinical diagnosis, but not strictly necessary to obtain Ultrasound not necessary, however, useful for assesment of nodules RAI uptake not indicated

Transient hypothyroidism
Silent (painless) thyroiditis = subacute lymphocytic thyroiditis (Hashimoto variant) Post partum thyroiditis, incidence 8-10%, need to differentiate from Graves, re-eval in 2-4wks Subacute granulomatous thyroiditis (Quervain), neck pain, diffuse goiter, ? Post viral, 15% permanent following subtotal thyroidectomy following RAI for Graves delayed TSH response

Transient hypothyroidism ctd

Infiltrative disease
Riedels fibrous thyroiditis, often euthyroid Infectious: strep, staph,TB, PCP Sarcoid (infiltrative vs associated AI dz) leukemia hemochromatosis

Iodine deficiency
Iodine deficiency most common cause of goiter & hypothyroidism worldwide Effect of I deficiency aggravated by goitrogen foods, with anti-thyroid properties (Africa, South America)

Goitrogens
Examples of foods that contain goitrogens Cruciferous vegetables including: Broccoli Brussel sprouts Cabbage Cauliflower Kale Kohlrabi Mustard Rutabaga Turnips Millet Cassava Peaches Peanuts Radishes Soybean and soy products, including tofu Spinach Strawberries

Iodine excess
High I inhibits organification Wolff Chaikoff effect protects normal subject from sudden I increase through iodination inhibition High I can cause hypothyroidism in preexistent Hashimotos Excess I in tonics, cough meds, kelp, topical betadine, radiocontrast, amiodarone (40%)

Iatrogenic thyroid dz
total thyroidectomy hypo in 2-4wks, variable in Graves: majority within 1yr, 0.5-1%/yr there after RAI for Graves hypo after months yrs, or transient RAI for toxic multinodular goiter hypo in significant minority external neck XRT, gradual, dose dependent, subclin for years. S/p Hodgkins XRT: 30% hypo/20yrs

Medication effects
Amiodarone: & effects, inhibits iodination hypothyroidism found in 7%/21months, mostly in pre-existing thyroid dz Loads autonomous nodules hyper thyroiditis hyper if euthyroid: T3, fT4, TSH= Lithium: I transport, T3/T4 release goiter in 50%, hypothyroidism in 20%. Do not withhold Li, treat with T4 Interferon , interleukin 2 de novo development of Ab (10-15%) 10% dvp dz

Monitor TSH Q 6-12 months

Medication effects ctd

TSH secretion inhibition: Dopamine, dobutamine, octreotide, glucocorticoids TSH : metoclopramide Metformin TSH, fT4= Absorption : iron, cholestyramine, ppi, calcium, high fiber diet Metabolism : anti-epileptic drugs TBG : estrogen, SERMs, methadone, 5FU TBG : androgens deiodinase inhibition: PTU, methimazol, propranolol
Monitor TSH in 4-6 wks after medication change

Medication effects ctd

blocks TBG binding: salicylates, some NSAIDs, furosemide fT4 heparin iv lipoprotein lipase stimulation ffa displace fT4

In short: Review the medication list !!

Treatment goals
improvement of symptoms normalisation of TSH reduction of goiter avoid oversuppletion : risk of A-fib in elderly risk of bone loss

T4 Treatment
No tx required for transient hypothyroidism In most cases life-long treatment T4 treatment reverses all clinical manifestations Synthetic T4 80% absorbed, on empty stomach, life is 7days Athyroid pt on T4 achieves pre-op T3 levels Advantage of pro-hormone: physiologic feedback mechanisms regulate T3 levels FDA approves brand substitution, endocrine societies dont

T4 Treatment ctd
Average adult dose: Hashi 1.6 mcg/kg/day central 1.9 athyroid 2.1 timing of dosing may affect fT4 level initial dose in young: may start full dose initial dose in frail & >50-60: start 50 or 25, go up by 12.5 25/ 3-6wks recovery starts in 2wks, full recovery in months full dose vs step-up: quicker lab improvement, clinical improvement equal Compliance problems: Q week dosing, but not in elderly.

Monitoring
Initially Q3-6wks, fT4 normalizes first, then TSH when stable: TSH Q 1 year recheck TSH within 4-6 wks of pertinent medication change, change of hormonal status Central hypothyroidism: monitor fT4

T3 replacement ?
Cytomel, Armour thyroid, Thyrolar Use is NOT recommended potency/bio-availability varies T3 treatment leads to wide T3 levels throughout the day fT4 levels remain low leads to confusion and inappropriate dosing adjustments

Evidence for treatment of suclinical hypothyroidism ?

Treatmant of Subclinical hypothyroidism

recent Cochrane review, cited in AFP journal 4/08: no survival or CV morbidity (cohort study) CV mortality for TSH>5, all cause mortality = QOL/emotional/symptom scores: equal small in cognitive function (1 small study)

Treatment: special situations

Pregnancy: T4 need @ 8wks, plateau @ 16 wks, TBG, T4 clearance, T4 transfer to fetus. Increase by T4 30% at pregnancy onset, TSH Q4wks, Q trimester when stable Surgical patient: if hypo: higher freq of ileus, hypotension, Na, CNS dysfx, F with serious infections, sensitivity to opiods & anaesthesia

Treatment: special situations ctd

Unclear indications: obesity, HLD. At least avoid oversuppletion !!!! Thyroid carcinoma: life long T4 to suppress TSH, if metas: TSH < 0.01, others 0.05-0.5, 10 yrs dz free: low normal range If worsening sx following start of T4 tx: suspect adrenal insufficiency / adrenal crisis. Myxedema coma: 80% mortality. T4 iv treatment, corticosteroids, do not wait for lab results

Bibliography
AFP journal UpToDate Publications form the American Thyroid Association, American Association of Clinical Endocrinologists, and the Endocirne Society Pathophysiology of Disease: An Introduction to Clinical Medicine, 5th Edition Stephen J. McPhee, William F. Ganong Emedicine

Kundalini yoga

Idiots think, saints do!

Yogi Bhajan