PowerPoint. Nonradioactive iodine competes with radioactive iodine. This has implications for the use of recombinant human TSH (rhTSH) when preparing differentiated thyroid cancer patients for radioiodine scanning with continued levothyroxine, because the latter contains iodine.

1. An I for an I*
Nonradioactive iodide competes with radioactive iodide
– implications for use of rhTSH with continued
levothyroxine
Herbert A. Klein, M.D., Ph.D
University of Pittsburgh, Department of Radiology

2. Objectives
• Understand the problem of nonradioactive iodide competing
with radioactive iodide for uptake in thyroid gland and
metastases.
• Understand the role in thyroid cancer management of low
iodine diet and avoidance of iodinated contrast; as well as the
role of iodine-containing medications including thyroid
hormone.
• Understand possible manipulations of thyroid hormone
therapy in relation to the use of recombinant human TSH for
imaging and therapy.

3. When we give I-131 for thyroid cancer we want to do the job at
hand as well as we can with the least harm possible. Part of that
goal is achieved by getting as much as possible of the I-131 that
we give into the target tissue, so as to require a smaller dose.
Also, for treating metastases, we may wish to maximize the
tolerable administered dose.

5. • Chemical and biochemical processes do not distinguish
isotopes of iodine.
• Dilution with cold iodine will predictably reduce uptake.
• This has implications for scan sensitivity and treatment
outcome.
• Therefore:
– Low iodine diet
– Avoid iodine-containing medications like amiodarone
– Avoid iodinated radiographic contrast

6. Background
Quantitative aspects of iodide intake and excretion
iodide is excreted 97% in urine, so
• intake output.
• A teaspoon of Morton’s iodized salt contains = 270 µg of
iodine.
• A typical multivitamin contains 150 µg of iodine.

7. Low iodine diet (highlights)
Avoid:
• Iodized salt
• Seafood
• Dairy products
• Cured meats
• Vitamins containing iodine
• Etc., Etc.

8. 24-h urinary excretion (µg/d)
• DTC pt’s off hormone:
– controls: 158.8 ± 9.0
– low iodine diet: 26.6 ± 11.6
– P<0.001.
(Pluijmen MJHM et al, Clinical Endocrinology 58:428-235, 2003)
• Better uptakes and more successful ablations have been
reported with low iodine diets.
• Case: A hyperthyroid patient’s 24-hour uptake went from
27% to 38% on a low iodine diet.

9. Will reducing 24-urinary excretion 5-fold cause a 5-fold
increase in uptake? In radiation dose?
Not so simple. There are other factors, e.g.
Sodium-iodide symporter may be down-regulated by iodide.
(Burman KD, “Low Iodine Diets,”in Wartofsky L and Van Nostrand D, Thyroid
Cancer: A Comprehensive Guide to Clinical Management, 2006)

10. 53 y.o. man, well differentiated papillary ca, encapsulated follicular variant, ~5 cm.
Relatively low thyroid bed activity; abnormal focus upper midline ant. thorax. Tg = 0.8.
Rx 202 mCi. Pre- and post-Rx scans.

11. This was 10.3 weeks after CT with contrast. Urinary iodine was
346µg/24 h (<400 considered important, under 50 desirable). 8
months later, scan negative, Tg <0.5, urinary iodine 86 µg/24 h.

12. Amdur RJ, Mazzaferri EL (Eds.), Essentials of Thyroid
Cancer Management, 2005, p.212:
“A single iodinated contrast exposure is likely to compromise
radioiodine uptake for 3-12 months…Measure a 24-hour
urine iodine level on day 7 of a low-iodine diet in any patient
with a history of iodinated contrast exposure in the past 6
months. Do not begin the preparatory program for
radioiodine administration unless the 24-hour urinary free
iodine level is ≤ 100 micrograms…”

14. Case 2
A 75-year-old man s/p thyroidectomy for a multifocal papillary
carcinoma, follicular variant, largest lesion 9 cm, with vascular
invasion. Following hormone withdrawal and low-iodine diet, his
initial I-123 scan showed widespread metastases. Tg = 1504
ng/ml (TSH = 11 µIU/ml). He was treated with I-131, 202 mCi. A
year later, Tg = 148 ng/ml (TSH 151 µIU/ml).
But: Complications happened in the interim.

15. Initial scan and therapy ~ 8/20/08.
• 3/25/09. CT with contrast,
• 6/9/09. 24-h. urine iodine 254 µg
• 8/20/09. 24-h. urine iodine 251 µg.
• Patient was on levothyroxine, 250 µg/d. TSH was 0.05 IU/ml
• Health issues including renal insufficiency precluded hormone
withdrawal.

16. O
HO
I
I
I
I
CH2
NH2
H
C COONa * xH2O
Levothyroxine: 63.5% iodine, absorption 40-80% , half-life 7 d.
O
HO
I
I
I
CH2
NH2
H
C COONa
Liothyronine: 56.6% iodine, absorption ~95%, half-life ~2.5 d.
“25 µg of liothyronine is equivalent to appoximately...0.1 mg of L-thyroxine.”
Source: Abbott Laboratories and King Pharmaceuticals Prescribing Information

17. Hormone regimen Est. hormone
contribution
Predicted 24 .
urinary I
Actual 24 h
urinary I
T4, 250 µg 159 µg (251 µg) 251 µg
T3, 50 µg 28 µg 120 µg <110 µg
Change in 24-hour urinary iodine (from baseline + hormone) due
to hormone switch

18. • Continuing liothyronine, using rhTSH, we did dosimetry and
therapy, only 130 mCi calculated to be tolerable (ascribed to
renal insufficiency).
• Perhaps this is the best we could have done for this patient.

20. • The advent of human recombinant TSH, enabling procedures
while patient has the benefits of continuing thyroid hormone,
raises the question of dealing with the iodine supplied by the
hormone.
• Method of Amdur and Mazzaferri, p. 236:

21. Barbaro D et al, J Clin endocrinol Metab 88:4110-4115, 2003.
DTC patients:
Groups 1 and 2 given I-131 30 mCi; 3 = control group: rhTSH
continuing T4
Group % ablated Urinary iodine
(µg/L)
P vs. control group
1: rhTSH, 4 d off T4 81.2% (n.s.) 47.2 ± 4.0 0.019
2: T4 withdrawal 75.0% 38.6 ± 4.0 <0.001
3: Control on T4 N/A 76.4 ± 9.3 ---

22. Critique of Barbaro et al
• Not a randomized controlled study
• Not a self-paired study!!
• 24-hour urine iodine was not used
• Only skimpy information about patient doses of levothyroxine

23. • Proposition: rhTSH should be used with conversion to
liothyronine, when possible, for three weeks. Radioiodine
specific activity should go up, hence increased uptake in
remnants and lesions, greater diagnostic sensitivity and more
effective therapy.
• Of course, none of this is relevant to the use of rhTSH for
thyroglobulin determination.

24. Ways to study withdrawal vs rhTSH with levothyroxine vs rhTSH
with hormone manipulations (e.g. liothyronine)
• Therapy outcomes (remnants or lesions)
– Self-pairing not possible.
– Randomized, controlled, prospective studies are rare (Pacini et al).
• Diagnostic (tracer dose) comparisons
– Self-pairing is possible.
– Stunning may be a problem.

25. • Diagnostic (tracer dose) comparisons (continued)
– Can study
a. Sensitivity for remnant and lesion detection
b. 24-hour urinary iodide
c. Renal I clearance
– Dosimetry
a. Remnant and lesion uptake values
b. Effective half-time and residence time in remnants and lesions
c. Radioactive dose to remnants and lesions
– Surrogate for comparative outcomes
d. Blood or bone marrow dose, as in conventional dosimetry.
– Allows comparison of allowed doses.

27. Residence time:
Area under the time-activity curve (e.g. in millicurie-days)
divided by amount of activity administered. Expressed, then, as
millicurie-days per millicurie, or megabequerel-hours per
megabequerel, etc. It is an important component of the
calculation of radiation dose.
For exponential curve as applied to whole body dosimetry (e.g.
Bexxar),
res. time = 1.443 x T-1/2-eff

28. For a remnant,
res. time = 1.443 x f x T-1/2-eff
So it is proportional to both the half-time and the fractional
uptake.
Confusing term. Proposed alternative term: normalized
cumulated activity
(Stabin MG, Fundamentals of Nuclear medicine Dosimetry, p. 36)

29. Ladenson PW et al, N Engl J Med, 337:888-96, 1997.
127 DTC patients underwent I-131 imaging (I-131, 2-4 mCi), first
with rhTSH, continuing thyroid hormone, subsequently after
withdrawal.
97 patients took levothyroxine, 6 triiodothyronine, 49 both.
In 62 patients with at least one positive scan,
Scans equivalent 41 (66%)
rhTSH scan superior 3 (5%)
Withdrawal scan superior 18 (29%) (P = 0.001)

30. “There are two possible explanations..
• …Radioactive clearance is decreased in hypothyroidism, resulting in higher
bioavailability of radioiodine…*
• ...Stimulation by [rhTSH] may be suboptimal.”
Dilution effect of iodine from thyroid hormone not mentioned.
*inferred from Park, S-G et al, J Nucl Med 37: Suppl: 15P (abstract), 1996, who
showed serum creatinine, whole body I-131 half-time and serum I-131 half-
time all increased by 1.5 after withdrawal vis-à-vis rhTSH.

31. Critique of Ladenson et al
• Self-pairing is a strength.
• The superiority of withdrawal might have been greater but for
stunning.

32. Haugen BR et al, J clin Endocrinol Metab 84:3877-3885, 1999.
Similar study, 220 patients, but standardized 4 mCi dose and
patients received either 2 or 3 rhTSH injections, and
compensatory slower scanning speeds were used after rhTSH.
In 108 patients with at least one positive scan,
Scans equivalent 83 (77%)
rhTSH scan superior 8 (7%)
Withdrawal scan superior 17 (16%) (NS)

33. Critique of Haugen et al
• Self-pairing is a strength.
• The superiority of withdrawal might have been greater but for
stunning.
• Slower scanning strategy acknowledges an advantage of
withdrawal.

34. Luster M et al, Eur J Nucl Med Mol Imaging, 30:1371-1377, 2003
9 patients, post-thyroidectomy, had kinetic studies before
ablation, first with 2 or 3 rhTSH injections, then withdrawal, and
using I-131 2 mCi. Form of thyroid hormone not stated.

35. After rhTSH vis-à-vis withdrawal
24- h uptake higher
Effective half-time higher
Residence time (determined by upt. & T-1/2) higher*
Blood dose lower
*Residence time determines radiation dose (calculation requires
mass) “The data suggest that radioiodine…is potent and safe
when administered to euthyroid patients following rhTSH…”

36. Critique of Luster et al
• Self-pairing is a strength.
• Small study (“pilot?”)
• “Reverse order studies should be performed to address the
possible impact of stunning.”

37. Hänscheid H et al, J Nucl Med, 47:648-654, 2006
and
Pacini F et al, J Clin Endocrinol Metab 91:926-932, 2006
• Randomized, controlled study of 63 patients after
thyroidectomy: withdrawal of levothyroxine or rhTHS, studied
following 100 mCi ablative dose (no diagnostic study).
• Remnant ablation 100% in both groups.

38. rhTSH Hormone
withdrawal
P
48 h remnant
uptake (%)
0.51 ± 0.70 0.91 ± 1.05 0.10
Effective T-1/2 (h) 67 ± 48.8 48.0 ± 52.6 0.01
Remnant residence
time (h)
0.86 ± 1.27 1.38 ± 1.51 0.11
Blood dose
(mGy/MBq)*
0.109 ± 0.028 0.167 ± 0.061 <0.0001
*similar for several methods reported

39. Remnant Ablation Trial
Radioiodine Kinetics

40. • “…The increased half-time in the rhTSH group does not fully
compensate for the lower uptake, and the mean remnant
residence time was longer in the THW group...A phase of a
persistently high TSH level…could promote release of
organified radioiodine from thyroid remnant tissue, thus
reducing the half-time.”
• “…The higher renal clearance in euthyroidism causes a faster
excretion…and significantly reduced radiation dose to the
blood… Higher activities of radioiodine might be administered
safely after stimulation by rhTSH.”

41. Critique of Hänscheid
• Randomized, controlled, but not self-paired (ablative dose)
• Stunning not an issue
• Without knowledge of remnant masses, residence times
could not be converted to radiation doses

42. Pacini et al
Urinary iodine concentrations
Group Urinary iodine
concentration (µg/dl)
P
rhTHS 12 ± 9 0.157
Hormone withdrawal 9 ± 8

43. Critique of Pacini
• 24-hour urine iodine not used.
• Hypothetical scenario:
– If patients had 24-hour urinary volume of 1.9 L and were taking T4 150
µg, that could account for the exact difference (57 µg/ d). Withdrawal
group’s level would be 171 µg/ d, which is high for a low iodine diet.
– That is, results are consistent with an obligatory difference due to T4.
(Patients were, in fact, reported to have had a low iodine diet for 2
weeks.)

44. Umlauf J et al, J Nucl Med 51 (Supp. 2): 146, 2010 (abstract)
• DTC patients treated with I-131 had lower creatinine and
faster clearance after rhTSH than total hormone withdrawal.

45. Mean values ±SD of Iodine Biokinetics in Whole Body and Blood After rhTSH and THW

47. Likely comparative points
• Withdrawal and rhTSH are comparable for remnant ablation
(and possibly for treatment of metastases)
• Withdrawal gives better uptake (which could make scans
more sensitive).
• rhTSH with sustained thyroid hormone gives longer effective
half-time in remnant, compensating with respect to therapy.
Conversely, prolonged elevated TSH may promote
turnover/washout of radioiodine.
• It also improves marrow dosimetry, presumably by faster
clearance of free radioiodine, by sustaining renal function,
allowing more radioiodine for the treatment of metastases.

48. Likely comparative points (continued)
• If renal iodide clearance is worse with withdrawal, that blunts
the benefit of lower iodine intake and urinary excretion.
• Substitution of liothyronine with rhTSH may improve the
situation, by maintaining the benefits of longer remnant half-
life and preserved renal function while also reducing
competing nonradioactive iodine, with a net effect of
increased uptake and residence time and thus radiation dose
per administered mCi.
Most of the relevant work has been with remnants. Question of
effects on metastases.

49. Suggested research
Self-paired study of 24-hour urinary iodine and of tracer I-131
kinetics in remnants (similar to Luster et al), using rhTSH with T4
vs T3, with the order randomized to control for stunning, with
ablation after the second test, and with kinetics of the therapy
dose also studied.

50. • “…The patients will be continuing to take exogenous L-T4 with
its significant iodine content during Thyrogen-stimulated
radioiodine scan or treatment. [An] option is to switch the
patients from T4 to T3 (which contains one less iodine
molecule)…”
Burman KD, “Low Iodine Diets,”in Wartofsky L and Van Nostrand D, Thyroid Cancer: A
Comprehensive Guide to Clinical Management

51. 24-hour urinary iodide is a step or two removed from what determines
the specific activity of administered activity in plasma.
[plasma iodide concentration] = [24-hour urinary iodide]÷[renal
iodide clearance]
[iodide pool] = [plasma iodide concentration] × [volume of
distribution]
Perry WF and Hughes JFS, J Clin Invest 31:457-463, 1952. (Renal clearance of iodide:
Mean of 11 normal controls was 31.4 ml/min.)
Maruca J et al, J Nucl Med 25:1089-1093, 1984. (Volume of distribution: About 25 l, as
determined in several thyroid cancer patients. Takes into account extracellular fluid.)

52. Effect of intake and urinary clearance on plasma concentration
and on iodide pool
Plasma iodide
concentration
Iodide pool Plasma iodide
concentration
Iodide pool
24-h urine
iodide 150 ug
3.32 ng/ml 82.9 µg 6.9 ng/ml 173.6 µg
24-h urine
iodide 30 ug
0.66 ng/ml 16.6 µg 1.39 ng./ml 34.7 µg
Clearance = 31.4 ml/min Clearance = 15 ml/min
Renal clearance can be an important variable affecting plasma concentration in
relation to urinary excretion.

53. Effect of added mass of iodine in administered radioiodine
Assume carrier-free I-131 (0.00806 ug/mCi) normal renal
clearance
24-hour urinary iodide (ug) Total ug in basic iodide pool After adding I-131, 200 mCi
150 82.9 84.5
30 16.6 18.2
Ratio 0.20 0.22
Carrier-free is “best case scenario.” High 200 mCi dose is “worst case scenario.”
I-123 is even better (factor of 15.7 for carrier-free).

55. Iodine prophylaxis – goitre prophylaxis
• Iodine prophylaxis –
• [Synonyms used: stable iodine prophylaxis, thyroid
blocking, iodine administration]
• Large dose of iodine that exceeds daily need about 1000
times, given once (or for a few days, max. one week) to
prevent or decrease uptake of radioactive iodine(s) into
thyroid gland and any consequent harm. Protective action for
nuclear emergency or after any accidental radioiodine intake
• Usual single dosage: 10-200 mg I/day depending on age (and
availability during emergency situation)
Source: “Overview of Nuclear Emergency Preparedness & Response, Iodine
Prophylaxis” Module XXI

56. • I-123 MIBG scan: “The patient will need to take potassium
iodide to protect the thyroid gland from the radioactive
iodine…”
• Bexxar (I-131-tositumommab), radioimmunotherapy of B-cell
lymphoma, given in large amounts: “Patients receiving Bexxar
therapeutic regimen should be premedicated…with SSKI
(saturated solution of potassium iodide), 3 drops in water 3
times a day [for several days]”, to protect against a very real
threat of hypothyroidism.