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					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
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)
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           Slow movement and slow speech
                                        Weight gain                   Delayed relaxation of tendon reflexes
    Slowing of metabolic processes
                                        Cognitive dysfunction         Bradycardia
                                        Mental retardation (infant)   Carotenemia
                                        Constipation
                                        Growth failure



                                        Dry skin                      Coarse skin
                                        Hoarseness                    Puffy facies and loss of eyebrows
    Accumulation of matrix substances
                                        Edema                         Periorbital edema
                                        Nerve entrapment              Enlargement of the tongue



                                        Decreased hearing
                                                                      Diastolic hypertension
                                        Myalgia and paresthesia
                                                                      Hair loss
                                        Depression
                                                                      Pleural and pericardial effusions
    Other                               Menorrhagia
                                                                      Ascites
                                        Arthralgia
                                                                      Galactorrhea
                                        Pubertal delay
                                                                      Ataxia
                                        infertility
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
                                 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 &                                                  Thyroid nodule

   incidentaloma                                                                    REFER to endocrinologist
                                                                                    for cost saving
     algorithm                                                 TSH (& anti TPO)




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

                             FNA                                   Uptake scan
                                                                                            Hashimoto’s             Tx w/ T4

                                                undiagnostic
                                                                        hot
                                                                                                    Scintigraphy may show nodule
Malignant 5%   Indeterminate       Benign 70%                                                       as 1 functioning lobe ->
               10%                                                                                  Biopsy not indicated
                                                                     observe
   surgery                         observation
               Uptake scan                                                                    ultrasound

    cold                                  hot                                      Infiltrate vs hyperplasia vs tumor vs
               indeterminate                                                       cyst.

                                                                                   Rapid shrinkage >50% with T4 tx is
               Suppression scan                                                    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                 excess iodine intake
goiter                 previous injury:
prior thyroiditis     (XRT, surgery,
H/O AI-dz, FH of AI   chemical exposure –
Down’s, Turner’s,     PCBs, resorcinol
primary PHTN, MS,     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 pre-
existent 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:  &                 Lithium:  I transport,
effects,                          T3/T4 release
inhibits iodination               goiter in 50%,
hypothyroidism found in           hypothyroidism in
7%/21months, mostly in            20%.
pre-existing thyroid dz           Do not withhold Li,
Loads autonomous                  treat with T4
nodules  hyper                   Interferon α,
thyroiditis hyper                interleukin 2  de
if euthyroid: T3, fT4,          novo development of
TSH=                              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
Kundalini yoga



Idiots think, saints do!   Yogi Bhajan

				
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