Hypothyroidism

Hypothyroidism

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 Hashimoto’s thyroiditis most common

cause of hypothyroidism and goiter in non- iodine deficient regions, USA

Appalachia: Hashimoto’s 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)

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.

Pathways of thyroid hormone metabolism

Major symptoms and signs of hypothyroidism

Mechanism Symptoms Signs

Slowing of metabolic processes

Fatigue and weaknessCold intoleranceDyspnea on exertionWeight gainCognitive dysfunctionMental retardation (infant)ConstipationGrowth failure

Slow movement and slow speechDelayed relaxation of tendon reflexesBradycardiaCarotenemia

Accumulation of matrix substances

Dry skinHoarsenessEdemaNerve entrapment

Coarse skinPuffy facies and loss of eyebrowsPeriorbital edemaEnlargement of the tongue

Other

Decreased hearingMyalgia and paresthesiaDepressionMenorrhagiaArthralgiaPubertal delayinfertility

Diastolic hypertensionHair lossPleural and pericardial effusionsAscitesGalactorrheaAtaxia

Diagnosis of hypothyroidism Diagnosis based on labs. Symptoms non-

specific 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

ScreeningThe 2002 consensus group's expert panel recommended against population-based screening but "encouraged" assessment in high-risk groups:Women > 60women 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)

Thyroid nodule

TSH (& anti TPO)

Normal TSH Decreased TSH High TSH &/or anti-TPO

Uptake scan

hot

observe

Malignant 5%

undiagnostic

FNA

Indeterminate 10%

Benign 70%

surgery Uptake scan

observation

indeterminate hot cold

Hashimoto’s

ultrasound

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

Tx w/ T4

Suppression scan

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

Nodule &incidentaloma

algorithmREFER to endocrinologist for cost saving

Causes of hypothyroidism

Chronic AI thyroiditis – Hashimoto’s

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

Down’s, Turner’s,

primary PHTN, MS,

excess iodine intake

previous injury:

(XRT, surgery,

chemical exposure –

PCBs, resorcinol

vigorous physical exam)

Hashimoto’s 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

Hashimoto’s disease ctd

Assoc w/ high I intake: anti thyroid antibodies

smoking assoc w/ onset of hypothyroidism in

pre-existent Hashimoto’s

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

Hashimoto’s 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

Riedel’s 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)

Examples of foods that contain goitrogens

Cruciferous vegetables including: •Broccoli •Brussel sprouts •Cabbage •Cauliflower •Kale •Kohlrabi •Mustard •Rutabaga •Turnips

MilletCassavaPeachesPeanutsRadishesSoybean and soy products, including tofuSpinachStrawberries

Goitrogens

Iodine excess

Wolff Chaikoff effect protects normal subject

from sudden I increase through iodination

inhibition

High I can cause hypothyroidism in pre-

existent Hashimoto’s Excess I in tonics,

cough meds, kelp, topical betadine,

radiocontrast,

amiodarone (40%)

High I inhibits organification

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 iodinationhypothyroidism found in 7%/21months, mostly in pre-existing thyroid dz Loads autonomous nodules hyperthyroiditis hyperif euthyroid: T3, fT4, TSH=

Lithium: I transport, T3/T4 releasegoiter in 50%, hypothyroidism in 20%.

Do not withhold Li, treat with T4Interferon α, 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, ½ 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 don’t

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 meta’s: TSH < 0.01, others 0.05-0.5, 10 yrs dz free: low normal rangeIf 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

Idiots think, saints do! Yogi Bhajan

Kundalini yoga