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Hypothyroidism

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Title: Hypothyroidism


1
Hypothyroidism
  • Kommerien Daling, MD
  • Chiefs Conference
  • August 14th 2008

2
Overview
  • Definitions
  • Epidemiology
  • Physiology
  • Symptomatology
  • Causes of hypothyroidism
  • Evaluation treatment
  • Screening

3
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

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

5
Epidemiology
  • 95 is primary hypothyroidism
  • Hashimotos thyroiditis most common
  • cause of hypothyroidism and goiter in non-
  • iodine 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 lt 50mcg/l

6
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.
7
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

8
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

9
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)

10
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.
11
Major symptoms and signs of hypothyroidism
12
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

13
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

14
DDx of elevated TSH
  • Primary hypothyroidism
  • Transient
  • Recovery from NTIS
  • Pituitary adenoma
  • Primary adrenal insufficiency
  • T4 resistance
  • TSH resistance at receptor level

15
fT4 low, TSH low
  • Central hypothyroidism
  • Imaging indicated to distinguish
  • hypothalamic from pituitary disease
  • Evaluate for 2dary adrenal insufficiency

16
Algorithm subclinical hypothyroidism
17
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

18
Screening
  • The 2002 consensus group's expert panel
    recommended against population-based screening
    but "encouraged" assessment in high-risk groups
  • Women gt 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
19
AAFP recommendation for Screening
it is common practice to screen patients with
dyslipidemia for hypothyroidism
20
Cost analysis 5 yr-ly screening
  • F _at_ 35yo 9,000/QALY (4000/2000)
  • F _at_ 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

21
Screening in the very elderly?
  • gt85 yo ? TSH associated with?? survival
  • evidence for benefit of not treating requires RCT

22
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)

23
Nodule incidentalomaalgorithm
REFER to endocrinologist for cost saving
24
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

25
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)

26
Hashimotos disease
  • Goitrous (more common) or atrophic
  • Humoral and cellular inflammatory proces
  • In 90 elevated, TPOgt TGBgt TSHR,
  • Na/I transporter antibodies
  • Cytotoxic T cells
  • high incidence in elderly women
  • ? estrogen deficiency

27
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

28
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

29
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

30
Transient hypothyroidism ctd
31
Infiltrative disease
  • Riedels fibrous thyroiditis, often euthyroid
  • Infectious strep, staph,TB, PCP
  • Sarcoid (infiltrative vs associated AI dz)
  • leukemia
  • hemochromatosis

32
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)

33
Goitrogens

34
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 pre-
  • existent Hashimotos Excess I in tonics,
  • cough meds, kelp, topical betadine,
  • radiocontrast,
  • amiodarone (40)

35
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

36
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 a, interleukin 2 ? de novo development
    of Ab (10-15) ? 10 dvp dz
  • Monitor TSH Q 6-12 months

37
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

38
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 !!
39
Treatment goals
  • improvement of symptoms
  • normalisation of TSH
  • reduction of goiter
  • avoid oversuppletion
  • risk of A-fib in elderly
  • risk of bone loss

40
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 dont

41
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 gt50-60 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.

42
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

43
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

44
Evidence for treatment of suclinical
hypothyroidism ?
45
Treatmant of Subclinical hypothyroidism
  • recent Cochrane review, cited in AFP journal
    4/08
  • no ?survival or ? CV morbidity (cohort study)
  • ?CV mortality for TSHgt5, all cause mortality
  • QOL/emotional/symptom scores equal
  • small ? in cognitive function (1 small study)

46
Treatment special situations
  • Pregnancy ?T4 need _at_ 8wks, plateau _at_ 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

47
Treatment special situations ctd
  • Unclear indications obesity, HLD. At least
    avoid oversuppletion !!!!
  • Thyroid carcinoma life long T4 to suppress TSH,
    if metas TSH lt 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

48
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

49
Kundalini yoga
Idiots think, saints do! Yogi Bhajan
50
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