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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 noniodine 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)
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
Slowing of metabolic processes
Fatigue and weakness
Cold intolerance
Dyspnea on exertion
Weight gain
Cognitive dysfunction
Mental retardation (infant)
Constipation
Growth failure
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
Thyroid nodule
REFER to endocrinologist
for cost saving
TSH (& anti TPO)
Normal TSH
Decreased TSH
FNA
Uptake scan
High TSH
&/or anti-TPO
Hashimoto’s
Tx w/ T4
undiagnostic
hot
Malignant 5%
Indeterminate
10%
surgery
Benign 70%
observe
Scintigraphy may show nodule
as 1 functioning lobe ->
Biopsy not indicated
observation
Uptake scan
cold
ultrasound
hot
indeterminate
Infiltrate vs hyperplasia vs tumor vs
cyst.
Suppression scan
Rapid shrinkage >50% with T4 tx is
reassuring, but not R/O malignancy
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)
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 Hashimoto’s 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 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 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
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