Hyperthyroidism

and Hypothyroidism

Gilbert H. Daniels M.D.

No Disclosures.

Gilbert H. Daniels M.D.

 Objectives

• To understand the differential diagnosis of hyperthyroidism

• To understand the growing role of drug-induced thyroid dysfunction

• To appreciate the significance of subclinical hyperthyroidism

• To understand what causes a change in L – T4 dosing.

• To understand the T4/T3 controversy for hypothyroidism

 Hyperthyroidism

TSH

T4
T3
 TSH Assays

1st 2nd 3rd 4th

generation generation generation generation
1965-1985 1984- 1989- 1992-
TSH uU/ml
10

0.1

0.01

0.001

Euth. Toxic Euth. Toxic Euth. Toxic Euth. Toxic

Hyperthyroidism - High or Normal RaI U

• Hot Nodule

• Toxic Nodular Goiter

• Graves Disease

• TSH Induced Hyperthyroidism

• HCG Induced Hyperthyroidism

Hyperthyroidism - High or Normal RaI U

• Hot Nodule

• Toxic Nodular Goiter

• Graves Disease

• TSH Induced Hyperthyroidism

• HCG Induced Hyperthyroidism

 HCG vs. TSH

40
hCG
cAMP (nmols/L)

30
TSH

20

10
Yoshikawa et al
JCEM 1989; 69: 891

TSH mu/L 1 10 100

hCG IU/L 10,000 100,000 1,000,000
 Hyperemesis Gravidarum

Mild Moderate Severe

25 * 250 1.5 TSH

FT4I FT3I
(uU/ml)
20 200 1.0

*
15 * 150 0.5

10 100 0.0
Goodwin et al Am J Ob Gyn 1992;167:646
 Pregnancy: TSH

9562 women - excluding hypothyroidism

10
5
3
TSH mIU/L

2
1.0
0.5 5th Centile
0.3
0.2
0.1

Lambert-Messerlian 11 12 13 14 15 16 17 18
et al Am J Ob Gyn Gestational age (completed weeks)
2008; 199: 62
 Hot Nodule

TSH

T4
T3
Hot Nodule
 Hot Nodule : Radioactive Iodine Therapy

3-17-59 7-28-59 4-14-60

RaI U 51 % RaI U 32 % RaI U 35 %

PBI 10.4 PBI 4.0 PBI 4.2
Rx 8 mCi 131 I

Hypothyroid : 5 % in our experience

 Toxic Nodular Goiter

TSH

T4
T3
Toxic Nodular Goiter
 Iodine Induced Hyperthyroidism
20 Vagenakis et al

KI 5gtts/d NEJM 1972;287:523

2 mos
15

T 4 Upper
10 limits of normal

Free T 4 Upper
limits of normal
0

Apr 69 June 69 Dec 69

 Graves’ Disease

123 I Uptake 78 %
Graves’ Ophthalmopathy
Thyroid Dermopathy: Pretibial Myxedema

Cheng CP et al NEJM 2005; 352: 918

 Thyroid Stimulating
Immunoglobulin

TSH
TSH Receptor

Thyroid Hormone

Thyroid Cell Other Receptor

 Elecsys TRab

Graves’Disease Painless Thyroiditis

GD Zone n = 382 n=1

(99.7%) (0.3%)
3.0 IU/L
Gray
n = 25 n = 11
zone
(69.4%) (30.6%)
positive
1.5 IU/L
Gray
n=7 n = 19
zone
(26.9%) (73.1%)
negative
0.8 IU/L

n=0 n = 218
PT Zone (0%) (100%)

Kamijo et al. Endocr Journal 2010; 57: 895

Graves’ Hyperthyroidism Therapy

• Block Synthesis

Methimazole or PTU

• Ablate or Remove the Thyroid

Radioiodine or Surgery
 Anti-Thyroid Drugs

Minor Toxicity ( 5 % )

• Fever

• Rash

• Joint Pains
 Anti-Thyroid Drugs

Major Toxicity

• Agranulocytosis ( 0.2 - 0.5 % )

• Pancreatitis (MMI) (0.2%)

• Toxic Hepatitis (PTU)

• Cholestatic Jaundice (MMI)

• Vasculitis (ANCA positive) (PTU)

 Propylthiouracil : 100 mg q 8 h
Methimazole : 30 mg q d
600

500 Nicholas et al S.Med J

1995; 88: 973
Serum T 3 (ng / ml)

400

300 Propylthiouracil
p = 0.12
200

Normal range Methimazole

100
p = 0.04 p = 0.058 p = 0.030

0 4 8 12
Weeks
 131 Iodine Therapy - Graves’ Disease

80

70
Percent Hypothyroid

60

50

40

30
Holm L-E et al
20 J Nuc Med 1982;
23:103
10

2 6 10 14 18 22 26
Years after Ra I
 Alemtuzumab : Reconstitution Autoimmunity

Anti-CD52 Antibody for MS

Thyroid dysfunction in 73/220 pts

Daniels et al.
40
J Clin Endocrinol Metab
34 %
2014; 99:80-9
Percent patients

30
22.2%
20

10 6.9 %
4.2%
0
Total Graves Hypothyroid SAT
 Hyperthyroidism Therapy

TSH Suppression

5.3 100.0
Free T4 ng / dl

TSH mU / L
4.0
10.0

3.7
1.0
1.3

0.10
0
< 0.05
0 12 24 36 48 60
Weeks
 Recent Patient

• High Free T4: > 7.8 ng/dL (0.9 – 1.8)

• High T3 > 650 ng/dL (60 - 181)

• Low TSH < 0.02 (0.4 – 5.0) mU/L

• High TBII 36 (< 1.75)

There is nothing wrong with this patient !!

The patient is on Biotin which (in high doses)

causes all these aberrant blood test results in
some drug platforms. TSI normal.

Barbesino Thyroid 2016: 26: 860

 Patient 1 Patient 2 Normal
Range

TSH < 0.01mU/L < 0.01mU/L 0.4-5 mU/L

T4 10.7 ug/dl 25.0 ug/dl 4-11 ug/dl

FT4 1.7 ng/dl 3.5 ng/dl 0.8-1.8 ng/dl

TT3 179 ng/dl 530 ng/dl 80-180 ng/dl

Subclinical Hyperthyroidism

• Low serum TSH

• Normal free T4

• Normal T3 or free T3
 Subclinical Hyperthyroidism

• Patient may or may

not be symptomatic !

• Exclude other causes of

decreased serum TSH.
 FT4 vs. TSH

500 > x 90
100
50
Serum TSH uU / ml

Spencer et al
10 JCEM 1990;
5 70: 453
1
0.5

0.1
0.05
x2
0.01
0.001
Undetectable
0 50 100 150 200 250 300 500 650

Free T4 nmol / L
 Subclinical Hyperthyroidism

• Uncertain effects on overall mortality.

• Some studies show increased cardiovascular mortality,

greater with TSH < 0.1 mU/L compared to 0.1 – 0.4

• Endogenous subclinical hyperthyroidism is associated

with osteoporosis and possibly fractures in post-

menopausal women, particularly with TSH < 0.1.

Ross DS Thyroid 2016: 26: 1343

 Atrial Fibrillation: Ten Year Prevalence
Age > 60

P = 0.005 Sawin et al NEJM

30 1994; 331: 1249
28 %
Percent

20

11 %
10

TSH < 0.1 TSH > 0.4 - 5.0

 Subclinical Hyperthyroidism

• As a general rule, the lower the serum TSH

(particularly < 0.1), the older the patient, the more
the concern about the heart or the bones, and the
longer the duration of subclinical hyperthyroidism
the more we are inclined to treat.

• For specific guidelines see Ross DS et al Thyroid

2016: 26: 1343.
 Subclinical Hyperthyroidism

• There are no large scale randomized,

placebo- controlled intervention trials.

Hyperthyroidism - 0 or near nil RaI U

• Factitious hyperthyroidism

• Painful subacute thyroiditis

• Painless subacute thyroiditis

• Amiodarone destructive thyroiditis

• Excess iodine

• Struma ovarii

• Metastatic follicular carcinoma

 Covid- 19 RelatedPainful Subacute Thyroiditis

• Painful Subacute thyroiditis may be an under-recognized

manifestation of Covid-19 infections.

• Generally occurs 16 – 36 days after resolution of

coronavirus infection, but in others simultaneous.

• The 4 cases described here had mild cases of Covid-19.

Brancatella A et al. J Clin Endocrinol Metab. 2020 Oct 1;105

 Destructive Thyroiditis

TSH

T3 and T4

RaI uptake = 0
 Destructive Thyroiditis : Subacute Thyroiditis

Hyperthyroid Hypothyroid Recovery

T4

TSH (uU/ml)
12
T4 (ug/dl)

TSH
8

4
3.5
0 0

0 3 6 9 12
Months
Destructive Thyroiditis

123 I Scan

4cm

SSN

24 hr RaI uptake 0.04 %

 Prevalence of Post-Partum Thyroiditis

Name Year Country FU Number Preg PPT

Screen

Amino 1982 Japan 6 507 N 5.5 %

Jansson 1984 Sweden 5 460 N 6.5 %
Freeman 1986 USA 3 212 N 1.9 %
Nikolai 1987 USA 3 238 N 6.7 %
Lervang 1987 Denmark 12 591 N 3.9 %
Fung 1988 UK 12 901 Y 16.7 %
Rasmussen 1990 Denmark 12 736 N 3.3 %
Rajatanavin 1990 Thailand 12 812 N 1.1 %
Roti 1991 Italy 12 372 N 4.8 %
Walfish 1992 Canada12 1376 N 6.0 %
Stagnaro-
Green 1992 USA 6 545 Y 8.8 %
 Post-Partum Thyroiditis: Antibodies

Stagnaro-Green A. Thyroid
Today 16: 1 : 1993

Prospective Studies
% Positive Antibodies

100

75

50

25

0 Amino Jameson Freeman Nikolai Lervang Fung Rasmussen Rajatanavin Roti Walfish Stagnaro-Green
1982 1984 1986 1987 1987 1988 1990 1990 1991 1991 1992
 Post-Partum Thyroiditis: Clinical

Hypothyroidism Hyperthyroidism
Alone Alone

36 % 38 %

26 %

Stagnaro-Green
Thyroid Today
Hyperthyroidism
16; 1 : 1993 then Hypothyroidism
 Immune Checkpoint Inhibitors

CTLA 4 PD-1 PDL-1

Ipilimumab Pembrolizumab Avelumab

Tremelimumab Nivolumab Atezolizumab
Pidizumab Durvalumab

Combinations

Ipilimumab + Nivolumab
Ipilimumab + Pembrolizumab
Tremelimumab + Durvalumab

Gonzalez-Rodriguez et al.Oncologist 2016: 21: 804

 Check-Point Inhibitor Hyperthyroidism

Almost all destructive thyroiditis, presumed autoimmune

16 Almost all go on to permanent hypothyroidism.
14 May correlate with improved cancer outcomes.

12
Incidence %

10
13.2%
8

4 3.2% Barroso-Sousa JAMA

Oncol 2018: 4: 173-182
2 1.7%
0.6%
0.0
CTLA-4 PD-1 PD-L1 Combination
Hyperthyroidism - 0 or near nil RaI U

• Factitious hyperthyroidism

• Painful subacute thyroiditis

• Painless subacute thyroiditis

• Amiodarone destructive thyroiditis

• Excess iodine

• Struma ovarii

• Metastatic follicular carcinoma

 Amiodarone Induced Thyrotoxicosis

Type 1 (10%) Type 2 (90%)

MNG Graves SAT

US Nodules No nodules No nodules

TRAb Neg Positive Negative

Ra I U Nil Nil Nil

Flow Nl or hi Nl or hi Low

Response None None Dramatic

to prednisone
 Amiodarone Induced Thyrotoxicosis Type 2

1.O Bogazzi et al
Prednisone 30 mg daily JCEM 2003;
88:1999
Mean Free T3 (ng/dL)

0.75

0.50

0.25

0
Amiodarone 0 7 14 21 30 60 90 180 240 360
Stopped Time (Days)
Secondary Hypothyroidism

TSH

T4
T3
 Ipilimumab

A 75 year old woman with Stage IV metastatic melanoma was

treated with ipilimumab an antibody against cytoxic T-lymphocyte-

associated antigen 4 (CTLA-4). Two weeks following her third

infusion she presented with bifrontal headaches. Her serum

sodium was 114. Her serum TSH was 0.2 with a nil free T4. Her

plasma cortisol was 2 ug/dl with an ACTH of 2 pg/ml (both very

low). She was diagnosed with pan-hypopituitarism and improved

with glucocorticoid and levothyroxine therapy.

 Ipilimumab Hypophysitis

Gutenberg et al. Am J Neuroradiology 2009, 30: 1766

 Hypophysitis

16
Barroso-Sousa JAMA
14 Oncol 2018: 4: 173-182

12
Incidence %

10
8.0%
8

6
3.8%
4

2 1.1%
0.0
CTLA-4 PD-1 Combination
Primary Hypothyroidism

TSH

T4
T3
Atrophic Primary Hypothyroidism

• Radioactive Iodine

• Surgery

• External Radiation

• Drugs

• Atrophic thyroiditis

• TSH Receptor Antibodies

• Mutant TSH receptor

• Congenital Hypothyroidism
 External Radiation: Hypothyroidism

80
Thyroid Volume 10 cc
Thyroid volume 15 cc
70 Thyroid volume 20 cc
Thyroid volume 25 cc
Hypothyroidism %

60

50

40

30 Boomsma MJ et al
Int J Rad Oncol Bio Phys
20 2012; 84: e 351

10

0
0 10 20 30 40 50 60 70
Mean Thyroid Dose (Gy)
 Sunitinib

Tyrosine kinase inhibitor licensed for therapy of

renal cell carcinoma and GIST tumors.

 Sunitinib Hypothyroidism
Desai et al.
Ann Int Med 2006

288
145:660
300

250 sunitinib

200 Levothyroxine
TSH U / L

150

100

52
50

48
19
8.8
6.2
2.5
3.9
4.3

2.3

0.6
1.0
1.6
1.3

10 20 30 40 50 60 70 80 90 100

Weeks
 Sunitinib Hypothyroidism

100 Risk close to 100% by life-table analysis

Percent with Hypothyroidism

75

50

25

0
36 52 96
Duration of rx. (weeks) Desai et al.
Ann Int Med 2006
Goitrous Primary Hypothyroidism

• Hashimoto’s Thyroiditis

• Painful Subacute Thyroiditis

• Silent Subacute Thyroiditis

• Drugs

• Transient Post RaI

• Biosynthetic Defects

• Iodine Deficiency

• Consumptive

• Congenital (Ectopic)
 Consumptive Hypothyroidism

Type 3 Deiodinase
Intrathoracic
Fibrous Tumor

Aw et al. JCEM 2014: 99: 3965

 Goitrous Primary Hypothyroidism

• Hashimoto’s Thyroiditis

• Hashimoto’s Thyroiditis

• Hashimoto’s Thyroiditis

• Hashimoto’s Thyroiditis

• Hashimoto’s Thyroiditis

• Hashimoto’s Thyroiditis Dr. Hakaru Hashimoto

Archiv fur Klinische Chirurigie
• Hashimoto’s Thyroiditis 1912; 97: 219
• Hashimoto’s Thyroiditis
Hashimoto’s Thyroiditis
 Premature Gray Hair

Hall et al. Color Atlas of Endocrinology 1979

 Vitiligo

Lancet 2002; 360: 1639

 Vitiligo

NEJM 2004; 26: 2698

 NIS Follicle
H202
Peroxidase
Apical
[ SI +] Surface

Colloid
Basal
Surface
Lumen

T3 MIT
DIT
T4 Daniels & Maloof 1976
 Anti-TPO Antibodies

10 5 n=181
Anti-TPO Antibodies U/ml

10 4

n=119
10 3
Mariotti et al
JCEM 1990;
71 : 661
10 2

n=98
10
<10
Control Graves’ Hashimoto’s
Is it worthwhile diagnosing Hashimoto’s

thyroiditis in euthyroid individuals ?

 Thyroid Antibodies: Miscarriages

Abramson and
Stagnaro Green
Thyroid 2001; 11: 57
T Ab + T Ab -
30
p < 0.01
25
Percent Miscarriage

p < 0.005
20
p < 0.05
p < 0.005 p < 0.05
15

10

0
Stagnaro- Glinoer Lejeune Singh lijima
Green
1991 1993 1995 1997 1990
 Thyroid Antibodies

Stagnaro-Green A.
Thyroid Today 16: 1 : 1993

Miscarriage Miscarriage
PPT
and PPT
60 60
50 50
Percent

40 40

Percent
30 30
20 20
10 10
0 0

Antibody Positive Antibody Negative

 Thyroid Failure
Normal Subclinical Moderate Severe
Hypothyroid Hypothyroid Hypothyroid
100
Serum TSH

20
Serum TSH
10

12
Serum fT4

8 Serum fT4

200
Serum T3

100 Serum T3

0
 Free T4 vs. TSH

500 > x 90
100
50
Serum TSH uU / ml

Spencer et al JCEM
10
1990; 70: 453
5

1
0.5

0.1
0.05
x2
0.01
0.001
Undetectable
0 50 100 150 200 250 300 500 650

Free T4 nmol / L
Subclinical Hypothyroidism

• Normal T4

• Normal Free T4

• Elevated TSH
 Subclinical Hypothyroidism

• Exclude other causes of

elevated TSH

• Patient may be symptomatic

or asymptomatic !!
 NHANES TSH > 4.5 mU/L
Total population: 17,353
16 Disease free: no thyroid disease,
goiter, thyroid meds :16.533
14

12
Percent

10

4
Hollowell et al
JCEM 2002; 87:489
2

0
12-19 20-29 30-39 40-49 50-59 60-69 70-79 80+
 Subclinical Hypothyroidism
Antibody Prevalence
100 96.5
NHANES III
85.2
Percent TPOAb + TgAb

80 Hollowell et al
JCEM 2002; 87: 489

60 54.6

40
28.0 30.9

20

0
TSH mU/L 4.0 - 4.5 4.5-5.0 5.0 - 10 10 - 20 > 20
 Community Practice

422,242 pts in Tel Aviv

5 year FU

3 % TSH > 5.5 - < 10 0.7 % TSH > 10 (overt)

n = 12,600 n = 2,950

Treatment started in 75% of those with abnormal TSH.

25% had only a single TSH determination !

Meyerovitch et al Arch Int

Med 2007;167: 1533
 5 Year untreated TSH > 10

Repeat TSH : > 10 5.5 - < 10 Normal

35 % 36.5 % 27.7 %

5 Year untreated TSH 5.5 - < 10

Repeat TSH : > 10 5.5 - < 10 Normal

2.9 % 35 % 62.1%

Overall 2.9 % of those not treated, progressed from

subclinical hypothyroidism to “overt” over 5 years

Meyerovitch et al Arch Int Med 2007;167: 1533

 Subclinical Hypothyroidism

• With TSH 4.7 - 10 mU/L : most are asymptomatic.

• No good evidence for L-T4 symptomatic benefit in this range.

• No good evidence for L-T4 cholesterol lowering in this range.

• There may be symptomatic and cholesterol benefit with TSH > 10.
Stott DJ et al. Thyroid hormone therapy for older adults

with subclinical hypothyroidism. New Engl. J Medicine

2017: 376: 2534

Persistent TSH 4.6 – 19.99 mIU/L (mean 6.4 + 2.01 mIU/L)

 Stott et al.

• Mean age 74.4 years

• Randomized placebo-controlled trial. Goal of therapy to
to normalize TSH.
• Major endpoints Hypothyroid Symptom Score or
Tiredness Score.

• Of note at baseline 27 % had nil hypothyroid symptoms

and 8.7% had nil tiredness score.

 Subclinical Hypothyroidism Elderly
Levothyroxine (n=332) Placebo (n = 337)
28.7 + 20.2 28.6 + 19.5
30

25 P = 0.99 P = 0.77

20 16.6 + 16.9 16.7+ 17.5

Score

15

10
Stott et al
NEJM 2017
5
epub

0
Hypothyroid Score Tiredness Score
12 months 12 months
 Stott et al.

• Recent (2020) subgroup analysis of those with

hypothyroid symptoms also showed no benefit
Moon et al. Subclinical hypothyroidism and

the risk of cardiovascular disease and

all-cause mortality: A meta-analysis of prospective

cohort studies. Thyroid 2018: 28: 1101.

 Subclinical Hypothyroidism: meta-analysis

• 35 articles.

• 555,530 participants.

• Subclinical hypothyroid: n = 21,176

• “High TSH with normal fT4” - not further stratified.

Moon et al. Thyroid 2018: 28: 1101.

 Subclinical Hypothyroidism Age < 65

• Increased cardiovascular mortality: RR 1.54 (CI 1.21-1.96)

• Increased all cause mortality : RR 1.28 (CI 1.1 – 1.48)

Moon et al. Thyroid 2018: 28: 1101.

 Subclinical Hypothyroidism Age > 65

• No significant association with CVD and all cause mortality.

• Low CVD risk: no association with mortality.

• High CVD risk: increased all cause mortality RR 1.41 (1.08-1.85)

but no increased CVD mortality: RR 1.5 (0.89-2.54)

• Note studies from the USA did not show increased mortality
but most had low CVD risk.

Moon et al. Thyroid 2018: 28: 1101.

 Fatal and non-fatal ischemic heart disease events
Subclinical Hypothyroidism: ages 40 – 70 (n = 3093)
TSH 5 – 10 mU/L

0.06 Multivariate analysis

No Levothyroxine Rx
Not a randomized trial
Cumulative Events

0.05

0.04 P = 0.02

0.03 Levothyroxine Rx

0.02
Razvi S et al.
0.01 Arch Int Med 2012;
172: 811
0.00
0 20 40 60 80 100
Follow-up months
Subclinical Hypothyroidism : Mortality Conclusions

• Ultimately requires an adequately powered,

randomized, placebo-controlled therapeutic trial !

• This is particularly difficult when some (many) patients

normalize their TSH over the course of the study.

What to do when TSH elevated

Patient on thyroid hormone:

generally increase dose.

What to do when TSH elevated

Patient not on thyroid hormone:

Repeat measurement.

Use common sense !

 My TSH is 6. I feel terrible.
Nothing is right. I’m cold,
tired, hungry, constipated
“Itsand
notdepressed.
wrking anymore !”
Please treat
me with thyroid hormone!

Subclinical Hypothyroidism
My TSH is 6. I feel fine !
Do I really have to be treated
with thyroid hormone for
the rest of my life ?

Subclinical Hypothyroidism
To treat or not to treat ?
 Subclinical Hypothyroidism
Treat ? Observe ?

Symptoms Yes No

Age Younger Older

TSH mU/L > 10 5 - 10

+ Thyroid Ab Yes No

Post-RaI Yes No

Goiter Yes No

Heart Disease No Yes

Pregnancy Yes No
 Thyroid Function in the Elderly

• In contrast to prior studies which seemed to show a

survival advantage in the elderly (over age 85).
• DuPuy et al. studied 2116 individuals > age 80:
Euthyroid 1811 (85.6%)
Subclinical Hypothyroid 136 (6.4%)
Overt Hypothyroid 105 (5.0%)
Subclinical Hyperthyroid 60 (2.8%)
Overt Hyperthyroid 4 (0.2%)
• No association with thyroid status and functional or
cognitive status outcomes or mortality.

DuPuy RS et al. Thyroid 2020 epub Nov 2.

 Subclinical Hypothyroidism

• With TSH 4.7 - 10 mU/L : most are asymptomatic.

• No good evidence for L-T4 symptomatic benefit in this range.

• No good evidence for L-T4 cholesterol lowering in this range.

• There may be symptomatic and cholesterol benefit with TSH > 10.

• On the other hand, in the absence of overtreatment, there is no

compelling evidence for harm with levothyroxine treatment.

• If you decide to treat, particularly in the elderly, if no benefit: stop!

 Elevated serum TSH

• Age 20-29 97.5 centile for TSH: 3.45 mU/L

• Age 80 + 97.5 centile for TSH: 7.5 mU/L

• Older patients: 70% with TSH > 4.5 mU/L

are within their age-specific reference range.

Surks and Hollowell JCEM 2007: 92: 4575

 Levothyroxine

• 7 day half life

• Single daily dose

• Absorption : 80 %

• We primarily use generic

 Thyroid Hormone Adjustment

• Worsening hypothyroidism

• Increased clearance

• Decreased absorption

• Pregnancy

• Age

• Poor compliance
 Increased Clearance

• Phenytoin

• Carbamazepine

• Rifampin

• Phenobarbital

• Imatinib

• Other Tyrosine Kinase Inhibitors

 Thyroid Hormone Adjustment

• Worsening hypothyroidism

• Increased clearance

• Decreased absorption

• Pregnancy

• Age

• Poor compliance
 Decreased Absorption

• Iron
• Aluminum hydroxide
• Calcium
• Lanthanum
• Cholestyramine and other resins
• Sucralfate
• Raloxifene
• Ciprofloxacin
• GI disorders - cryptic sprue
• Decreased stomach acid
• Food - including espresso
• “Insoluble Pills”
Increased Levothyroxine Requirement

• Estrogen

• ? Sertraline
 Thyroid Hormone Therapy

50.0

40.0
Serum TSH U/L

30.0

20.0

10.0
Mandel et al NEJM
5.0
0.5 1990; 323: 91
0.0
Before During
pregnancy pregnancy
 High L-T4 Requirement in a Community Setting

T4 dose > 225 mcg

N = 125
Robertson HMA et al
Thyroid 2014; 24: 1765
50

40 36.1%
Percent

30
20.8 % 21.6%
20 16.8 %

10 4.7%

0
Interfering meds Compliance Parietal Ab Celiac No cause
 Fable

Once upon a time there was a symptomatic hypothyroid

patient with an elevated serum TSH. Thyroid hormone

therapy was begun. The TSH normalized, the symptoms

disappeared and the patient lived happily ever after !

88 – 90 % feel well on levothyroxine therapy.

 Levothyroxine Therapy
Thyroid Symptom Questionnaire

50 46.8 48.6
Patients
Percent TSQ > 3

40 Controls
35.0 35.0
Patients - “Nl”TSH
30

20 462 patients
535 controls
10

Saravan et al.
0 Clin Endocrinol
p=<0.001 p<0.001 2002; 57: 577
 Possible Explanations

• Failure to titrate TSH to “low normal”

• T 3 supplementation required

• Co-morbid disorders including depression

• Having an illness ( “Labeling” )

• Coincidence (“squeaky wheel gets tested”)

• Hashimoto’s thyroiditis
 Levothyroxine Dose Titration

No Difference

Weight
Zulewski score
Visual Analog Scale
SF-36 Questionnaire
5.0 GHQ-28
Thyroid Symptom Q
4.0 Treatment Satisfaction
2.8 + 0.4
TSH mU/L

3.0

2.0
1.0 + 0.2
1.0 0.3 + 0.1
0.0 Walsh et al. JCEM
Low Medium High 2006; 91:2624-30
 Possible Explanations

• Failure to titrate TSH to “low normal”

• T 3 supplementation required

• Co-morbid disorders including depression

• Having an illness ( “Labeling” )

• Coincidence (“squeaky wheel gets tested”)

Super Hormone
Improvement No improvement Prefer T4/T3
in metrics in metrics

Bunevicius Bunevicius
Escobar Escobar
Saravanan
Siegmund
Walsh*
Sawka
Clyde
Apelhof Apelhof
Rodriguez

* some categories worse

 T 4 + T 3 vs. T4 Therapy

• Overall, most trials do not show benefit by the tested metrics.

• In some trials T4 + T3 preferred despite no benefit by metrics

• Some patients feel better for a while and then benefit disappears

Jonklass Thyroid
2014: 24: 1670
Panicker V. et al. Common variations in the DIO2 gene predicts

baseline psychological well-being and response to

combination thyroxine plus triiodothyronine therapy in

hypothyroid patients. J Clin Endocrinol Metab 2009; 94: 1623

 General Health Questionnaire

Deiodinase Genotype
Panicker et al JCEM
2009 ; 94: 1623 T4 + T3
P = 0.03
T4
TT TC CC

15
GHQ Score

13

11

9
1 2 3 1 2 3 1 2 3
Visit Visit Visit
 Satisfaction

Deiodinase Genotype
Panicker et al JCEM
T4 + T3
2009 ; 94: 1623
T4
P = 0.02

TT TC CC

3.5
3.4
3.3
3.2
3.1
3.0
1 2 3 1 2 3 1 2 3
Visit Visit Visit
 Concerns about T3 Trials

• None have specifically analyzed patients who do not feel

well on levothyroxine.

• Although T3 is generally lower in the L-T4 treated group,

there are no studies targeting those with lower T3 and no
evidence that those with lower T3 respond better.
 T4 + T3 Conclusions

• There may be some patients who (are genetically

pre-disposed to) feel better on the combination therapy.
Whether this is due to a physiological role of T3 or a
pharmacological property of T3 in some individuals is
uncertain.

• There is a strong placebo effect.

• Even if we agree that T3 is necessary, we do not know the ideal

way to prescribe T3.
 What I do when patients don’t feel well on T4

• Realize that many patients don’t feel well (with or without T4)

• Look for other concomitant disorders: these include

iron deficiency and anemia in pre-menopausal women, sleep
disturbances including sleep apnea, and depression.

• Titrate TSH to lower normal range (despite the controlled studies)

• Consider adding T3 (liothyronine) 5 mcg in the a.m. and 5 mcg in

early afternoon. Initially I don’t adjust the levothyroxine dose
(unless TSH very low at the time) but ask patients to call in two
months. If feeling better I check TFTs and continue the
medication. If no difference I stop the medication.
Guldvog I et al. Thyroidectomy versus medical

management for euthyroid patients with Hashimoto Disease

and persisting symptoms. Ann Int Med 2019; 170: 453

 Hashimoto’s Disease: Surgery vs. Medical Rx.

• 150 patients (age 18 – 79)

• On levothyroxine for hypothyroidism

• TPO Ab > 1000 IU/ml

• Symptoms “severe enough” to warrant surgery (NOS)

• At the “end of road”, with “high motivation for surgery.”

• Total thyroidectomy vs. medical management

• Short Form - 36 Health Survey at 18 months and TPO titer

Gudlvog I et al. Ann Int Med 2019; 170: 453

 Hashimoto’s Disease: Surgery vs. Medical Rx.

• Surgical group improved SF – 36

• Fatigue score decreased

• Chronic fatigue decreased from 82 % to 35 %

• TPO Antibodies decreased from 2232 to 152

• 3 surgical infections (4.1%); 3 longstanding

hypocalcemia (4.1%) 4 unilateral RLN palsy (5.5%)

• Note: this is with a group of expert surgeons.

Gudlvog I et al. Ann Int Med 2019; 170: 453

Vitality

Social Functioning

Emotional Score Mental Health Score

Gudlvog I et al.
Ann Int Med 2019; 170: 453
 Hashimoto’s Disease: Surgery vs. Medical Rx.

• Caveat: before considering this approach it is imperative to

realize that total thyroidectomy for patients with
Hashimoto’s thyroiditis is much more difficult than a
conventional total thyroidectomy due to surrounding
inflammation. (McManus C. Surg Res 2012; 178: 529)
 Summary Points

• Hyperthyroidism is not just Graves’ disease

• Many drugs cause thyroid dysfunction (e.g. amiodarone,

alemtuzumab, sunitinib, immune check point inhibitors and others).

• Hypothyroidisim is primarily Hashimoto’s thyroiditis but think of

other etiologies.

• For inappropriate TSH elevation in patients on thyroid hormone,

consider increased metabolism, decreased absorption, pregnancy
or poor compliance

• Possible but limited role for T3 supplementation.

 Hyperthyroidism

and Hypothyroidism