Hyperthyroidism Beyond the TSH SISK 11162009 Mark Lepsch

1
Hyperthyroidism Beyond the TSH SISK -
11/16/2009Mark Lepsch
2
The Triage Approach to Thyroid Disease
Hypothyroidism
SymptomsFatigue, weight gain, constipation, dry
skin
LabsHigh TSH


Increase Synthroid Dose
Hyperthyroidism
Endocrine referral for ablation, resection, or
funny drugs I havent seen since medical
school, followed by return to me in 1 year with
SymptomsAnxious, weight loss, diarrhea,
diaphoresis
LabsLow TSH


3
Triage vs. Understanding of Thyroid Disease
History, PE
T3, Free T4
TSH reflex
TBG, SHBG
Hot/cold nodules
Low vs. high uptake
Thyroglobulin
Thyroid Scan
PTU, Tapazole
Antibody titres
T3RU
RAIU I-123
RAIA I-131
Refer for surgery/ablation
Adjust Synthroid dose
4
Presentation Overview
(1) Present cases (2) Review thyroid gland and
diagnostic workup from family physician/endocrinol
ogist standpoint. (3) Re-assess cases with our
new-found knowledge (4) Discuss etiologies and
treatments
5
Case 1
C.S. is a 23 yo female pharmacist who presents to
the clinic following 6 months of feeling
anxious and hyper. She complains of loose
stools, insomnia, and difficulty with
concentration. She has a TSH which is low at
0.05. One week later she returns to the lab and
has a TSH reflex which is low at 0.17, with a T4
that is normal at 1.1. She also tests positive
for antibodies to Thyroglobulin (TG) and Thyroid
peroxidase (TPO). One month later her TSH is
back within the normal range. What is her
diagnosis? What other labs would you like?
6
Case 2
B.S. is a 23 year old athletic young track star
who presents with a several month history of
progressive hyperthyroid symptoms diarrhea,
heat intolerance, anxious, fidgeting, trouble
concentrating, etc. Her TSH is low at 0.05, with
a free T4 that is high at 3.0. Her TSI antibody
test is positive. What is her diagnosis? What
other labs would you like?
7
Case 3
P. Ham is a 33 yo G3P2002 who presents to your
clinic at 13 weeks complaining of feeling big
changes. She is feeling much more energetic,
even jittery at times. She is having bid stools
(as opposed to q3d during the first trimester),
feeling anxious, and occasionally feeling hot and
flushed. She is very concerned about her thyroid
as she knows that IgG antibodies can cross the
placenta and potentially damage a fetal thyroid
gland. Her T3RU is low but her TSH and T4 are
normal. What is her diagnosis? What other labs
would you like?
8
Presentation Overview
(1) Present cases (2a) Review thyroid gland
(2b) Review diagnostic workup for
hyperthyroidism from family physician/endocrinolog
ist standpoint. (3) Re-assess cases with our
new-found knowledge (4) Discuss etiologies and
treatments
9
Thyroid Gland Overview
10
Quiz Question
Question The thyroid gland is located in the A
neck B abdomen C ischiorectal fossa D the
supercharger of Shars subaru
Answer A - neck
11
Quiz Question
Question The thyroid gland has 2 types of cells
1. Follicular cells, which pump in Iodine and
synthesize _______ and _____ to be released into
circulation to regulate basal metabolic rate. 2.
Parafollicular "C" cells - (C for clear) -
synthesize and secrete ______ which acts to
reduce osteoclastic activity.
Answer 1. Tri-iodothyronine (T3) and thyroxine
(T4) 2. Calcitonin
12
Thyroid Gland - Overview
The functional units of the thyroid gland are
thyroid follicles - irregular spheroidal
structures composed of a single layer of cuboidal
epithelial cells bounded by a basement membrane.
The follicles are filled with a glycoprotein
complex called thyroglobulin which stores thyroid
hormone prior to secretion. Thyroid gland has 2
types of cells1. Follicular cells - pump in
Iodine (I-), synthesize thyroid hormone (T3,
T4).2. Parafollicular "C" cells - (C for clear)
- sythesize and secrete calcitonin reduces serum
Ca2 levels.
13
Quiz Question
Question The first major enzyme in the
production of thyroid hormone is called thyroid
peroxidase. This enzyme is inhibited by which
two medicines?
Answer PTU (Propylthiouracil) and Methimazole
(Tapazole)
14
Thyroid Gland - Overview

• Iodide (I-) is pumped into thyroid follicular
  cells.
• 2I- are oxidized to I2, via thyroid peroxidase,
  which is inhibited by propylthiouracil and
  Methimazole.
• I2 tyrosine forms Monoiodotyrosine (MIT) and
  Diiodotyrosine (DIT).
• MIT DIT form T3 (Triiodothyronine) and T4
  (Thyroxine). Note, T3 and T4 are formed on
  thyroglobulin, which is stored in follicular
  lumen.
• Upon TSH stimulation, iodinated thyroglobulin
  (T3-thyroglobulin, T4-thyroglobulin) is taken
  back into follicular cells. Lysosomal enzymes
  degrade thyroglobulin, releasing T3 and T4 into
  circulation.

I-
T3-TGBT4-TGB
T3, T4
15
Thyroid Gland Overview (2)

• Leftover MIT and DIT are degraded by thyroid
  deiodinase, releasing I2. Deficiency of thyroid
  deiodinase can mimic I2 deficiency.
• In circulation, T3 and T4 are bound to TBG
  (Thyroxine-Binding-Globulin). In hepatic
  failure, TBG is deficient and total T3, T4
  decrease. In pregnancy, TBG is increased, and
  total T3, T4 are increased.
• More T4 is synthesized than T3, although T3 is
  3-4x more active than T4. In peripheral tissues,
  T4 is converted to T3 or reverse T3 (rT3), which
  is inactive.
• 99 of T4 is bound, and 98 of T3 is bound to
  protein only the free forms (unbound) are
  active. 3 proteins which bind thyroid hormone-
  TBG Thyroid Binding Globulin- Thyroxine
  Binding Prealbumin- Albumin

16
Questions?
17
Hyperthyroidism - Overview
Thyrotoxicosis general term for increased
levels of triiodothyronine (T3) and/or thyroxine
(T4). Hyperthyroidism refers to causes of
thyrotoxicosis in which thyroid produces too much
thyroid hormone. Thyroid autonomy refers to
spontaneous synthesis and release of T3/T4
independent of TSH levels. We can have 2 types
of hyperthyroidism high-uptake and low-uptake.
18
Presentation Overview
(1) Present cases (2a) Review thyroid gland
(2b) Review diagnostic workup for
hyperthyroidism from family physician/endocrinolog
ist standpoint. (3) Re-assess cases with our
new-found knowledge (4) Discuss etiologies and
treatments
19
Thyroid Disease Diagnosis Quotation
A very famous, very intelligent physician once
said You can spend a lot of money doing them
endocrine workups
Quiz Question Name the time, date, person,
location, and level of evidence
Quiz Answer 1349pm, 10/29/04, Dr. Steve Heim,
precepting room. LOE H (Harper/Ham/Heim)
20
Hyperthyroidism - Workup
(1) Hx/PE (2) Labs (3) Imaging (4) Antibody tests
21
Hyperthyroidism Hx/PE
- Nervousness, Palpitations, shakiness, Fine
tremor Irritability, emotional lability
Fatigue, muscle weakness Diarrhea, Weight loss
w/good appetite Heat intolerance Trouble
concentrating Brittle, fine hair Tachycardia,
flow murmurs Warm, moist skin Hyperreflexia
with rapid relaxation phases Goiter (with a
bruit in Graves dx)Note, weight gain is
possible if compensatory polyphagia is large
enough.
22
Hyperthyroidism Screening Labs
1. Decreased TSH 2. Increased Free T4, Free T33.
Increased T3RU 4. Other lab abnormalities-
Mild leukopenia Normocytic anemia Elevations
in hepatic transaminases and bone alkaline
phosphatase Mild hypercalcemia Low albumin
Low cholesterol
23
Hyperthyroidism T3 Resin Uptake
T3RU T3 Resin Uptake1. Normally, T4 is bound
to TBG in serum, but some binding sites are
open.2. We administer radiolabelled T3, of
which some binds to the open binding sites on
TBG.3. We then measure the radiolabelled T3
that did not bind- If low, we had increased T4
binding capacity (Excess TBG) If high, we had
reduced T4 binding capacity (low TBG)
Bound to T4
Open
24
Hyperthyroidism TSH, T4/T3, FT4/FT3, T3RU
25
Quiz Question
Question The first step in sorting out the
etiology of hyperthyroidism is to decide if the
cause is a high-uptake or low-uptake cause.
Which test is used for this? Be specific.
Answer RAIU (Radioactive Iodine Uptake) test.
Note this is NOT a thyroid scan.
26
Hyperthyroidism - Workup
Radioactive Iodine Uptake Test administer
radiolabelled iodine (I-123)and measure the level
24 hours later. Usually, thyroid follicles take
up about 10-30 of administered dose. If the
thyroid takes up gt30, this indicates
hyperfunction. Note - this is a FUNCTION test,
not an IMAGING test. HIGH-UPTAKE
HYPERTHYROIDISM - DDX - Graves dx. Toxic
multinodular goiter. Solitary toxic
adenoma. LOW-UPTAKE HYPERTHYROIDISM - DDX -
Factitious hyperthyroidism Iodine-induced
hyperthyroidism Thyroiditis Disruptive,
subacute, painless, post-partum
27
Hyperthyroidism - Workup
Thyroid Scan 1. Administer a radioactive isotope
that localizes in thyroid gland.2. Image the
thyroid. DIFFUSE vs. SOLITARY IMAGE These
patterns are seen in high uptake
hyperthyroidism. 1. Diffuse tracer uptake
indicates Graves dx.2. Mutiple discrete
nodules toxic multinodular goiter3. Single
area of intense uptake Solitary toxic
adenoma. NODULE EVALUATION Cold nodule
nonfunctional. Scary, because 20 risk of
carcinoma.Hot nodule functional. not
malignant, but must be folllowed because can
cause thyrotoxicosis.
28
I-123 Thyroid Scan
29
Hyperthyroidism - Antibodies

• Anti-Thyroglobulin Antibodies (TG)
• Anti-Thyroid Peroxidase Antibodies (TPO), aka
  Anti-Microsomal Antibodies
• Thyroid Stimulating Immunoglobulins (TSI), aka
  Anti-TSH Receptor Antibodies (TSHR-Ab)
• Formerly called LATS (Long Acting Thyroid
  Stimulator) in 1950s, later discovered to be an
  IgG

30
Hyperthyroidism Antibodies
31
Questions?
32
Presentation Overview
(1) Present cases (2a) Review thyroid gland
(2b) Review diagnostic workup for
hyperthyroidism from family physician/endocrinolog
ist standpoint. (3) Re-assess cases with our
new-found knowledge (4) Discuss etiologies and
treatments
33
Case 1
C.S. is a 23 yo female pharmacist who presents to
the clinic following 6 months of feeling
anxious and hyper. She complains of loose
stools, insomnia, and difficulty with
concentration. She has a TSH which is low at
0.05. One week later she returns to the lab and
has a TSH reflex which is low at 0.17, with a T4
that is normal at 1.1. She also tests positive
for antibodies to Thyroglobulin (TG) and Thyroid
peroxidase (TPO). One month later her TSH is
back within the normal range. Thyroiditis stay
tuned for details.
34
Case 2
B.S. is a 23 year old athletic young track star
who presents with a several month history of
progressive hyperthyroid symptoms diarrhea,
heat intolerance, anxious, fidgeting, trouble
concentrating, etc. Her TSH is low at 0.05, with
a free T4 that is high at 3.0. Her TSHR
antibody test is positive. Graves disease
35
Case 3
P. Ham is a 33 yo G3P2002 who presents to your
clinic at 13 weeks complaining of feeling big
changes. She is feeling much more energetic,
even jittery at times. She is having bid stools
(as opposed to q3d during the first trimester),
feeling anxious, and occasionally feeling hot and
flushed. She is very concerned about her thyroid
as she knows that IgG antibodies can cross the
placenta and potentially damage a fetal thyroid
gland. Her T3RU is low but her TSH and T4 are
normal. Normal thyroid changes associated with
pregnancy
36
Presentation Overview
(1) Present cases (2a) Review thyroid gland
(2b) Review diagnostic workup for
hyperthyroidism from family physician/endocrinolog
ist standpoint. (3) Re-assess cases with our
new-found knowledge (4) Discuss etiologies and
treatments
37
Hyperthyroidism Etiologies
Thyroid uptake low 4. Factitous 5.
Iodine induced high 6. Thyroiditis Thyroid
scan 1. Diffuse tracer uptake Graves
dx.2. Mutiple discrete nodules toxic
multinodular goiter3. Single area of intense
uptake Solitary toxic adenoma.
TPO, TG
TSHR-Ab
Antibody tests
7. Pregnancy
38
Thyroid Diseases - Etiologies
Graves Disease Thyroiditis Pregnancy
39
Thyroid Diseases - Graves
Etiology Patient produces IgG antibodies which
are agonists to the TSH receptor.
Classic Triad (15-20) Diffuse Thyroid
enlargement, Hyperthyroidism, and Ophthalmopathy
Short term- Beta blockers - to reduce
peripheral T4?T3 conversion.Long term-
Thionamides - PTU or Methimazole - remission at 1
year in 33, but 5-10 have serious side fx.-
RIA (Radioactive Iodine Ablation), w/ I131.
Hypothyroid in 50.- Surgery, but risks are
greater than RIA.
40
Thyroid Diseases Graves Rx
Torring, et al. J Clinical Endo. and Metabolism,
1996 81 2986. Prospective, Randomized Trial,
179 patients. Thionamides RAIA (I-131) Surgical
Resection (1) All equally effective at
normalizing serum T4 at 6 weeks. (2) gt95 of
patients in all groups satisfied w/ therapy (3)
Would you recommend this treatment to a friend (
saying yes) 68 84 74 (4) Relapse rate over
4 years 40 20 5 (5) In USA, thionamides
used to obtain euthyroid state, then 70 of
thyroid specialists choose RAIA. (6) In Europe,
thionamides used to obtain euthyroid state, then
20 patients move to RAIA.
41
Thyroid Diseases - Etiologies
Graves Disease Thyroiditis Pregnancy
42
Quiz Question
Question What is the most common cause of
hypothyroidism in iodine-sufficient populations?
Answer Hashimotos thyroiditis
43
Thyroid Diseases Thyroiditis
Literally, thyroiditis means inflammation of the
thyroid gland. Etiologies- Acute thyroiditis
(Suppurative) Staph, Strep, MTB, T.P.
Autoimmune thyroiditis Hashimotos, Atrophic,
Juvenile - Drug induced thyroiditis -
Amiodarone Painless Thyroiditis Postpartum
thyroiditis Type I DM Subacute thyroiditis
(Granulomatous) - Viral - Reidels stroma
Fibrosis of gland Rx 1. In thyrotoxic stage,
beta-blockers relieve adrenergic symptoms.
Steroids? 2. No ablative therapy (drugs,
radioiodine ablation, surgery)3. Watch for
recovery hypothyroidism consider synthroid.
44
Thyroid Diseases Subacute Thyroiditis
Hx/PE Low-grade fever, Pain in gland, Sx of
hyper or hypothyroidism. Stages (1)
Inflammatory destruction causes release of T4, T3
into blood, thyrotoxicosis may ensue.(2)
Transitory period (1-2) weeks of euthyroidism
occurs after extra T4 is cleared from body.(3)
Patients become hypothyroid as gland repairs
itself (6-12mo)(4) Euthyroid state returns, with
subtle abnormalities (See prognosis). Prognosis
Clinically patients recover fully, but serum
thyroglobulin levels remain elevated and
intrathyroidal iodine content is low for many
months.
45
Thyroid Diseases Hashimotos Thyroiditis
Hx Age 40-50s, more common in women. Familial
predisposition, associated with certain HLA
haplotypes. Pathology Autoimmune destruction of
gland, leading to hypothyroidism.
46
Thyroid Diseases - Etiologies
Graves Disease Thyroiditis Pregnancy
47
Thyroid Diseases Pregnancy
Normal TRH and TBG both increase. TBG is
increased as much as twofold, thus leading to
elevated total T4 and T3. This leads to slightly
increased binding of T4 and T3, thus potentially
leading to slightly low Free levels of T4 and T3.
However, the increased TRH usually increases T4
and T3 production enough to keep the free levels
within normal range or even slightly high. This
can cause transient decrease in TSH (10-20 of
women). Graves disease Most common hyperthyroid
etiology in pregnancy (occurs in 0.2) Diagnosis
made by TSH lt 0.01 and elevated free T3 or T4
levels. Iodine studies Contraindicated during
pregnancy.
48
Thyroid - EBM

• Avoid Calcium carbonate co-administration with
  levothyroxine. (LOE 1b)
• Overtreating w/ Synthroid (suppression of TSH)
  inc. osteoporosis (LOE 4)
• ACP screening All women over age 50 w/ TSH
  (LOE 1a)
• USPSTF screening None (LOE 1a)
• Levothyroxine (T4) Levothyroxine
  Liothyronine (T3)

49
More Pictures