Controversies in theManagement of Hyperthyroidism

Two Challenging Cases

David S. Cooper, M.D.

The Johns Hopkins UniversitySchool of Medicine

80 year old man

• An 80 year old man with a history of MI andventricular arrhythmias presented with a 1month history of a 15 lb. Weight loss andweakness.

• He had been on amiodarone 200 mg bid for24 months. Thyroid function tests 6 monthsearlier had been normal, but now a serumTSH was <0.002 mU/l.

80 year old man• The cardiologist felt that it was not possible to

discontinue the amiodarone, and the patientwas referred for an endocrine evaluation.

• The patient’s PH was otherwiseunremarkable.

• Medications: atenolol, atorvastatin, ranitidine

80 year old man• PE: Pulse 60/min BP 120/70 weight 126.

No proptosis. The thyroid was not palpableand no nodules were appreciated. The heart,lungs, and abdomen were normal. There wasno tremor and no edema.

• Free T4 3.0 ng/dl (.8-1.8) T3 190 ng/dl (80-180)

• IL-6: normal (returned 2 weeks later)

80 year old man

• Ultrasound showed a normal sizedthyroid with scattered subcentimeternodules bilaterally.

• A continuous flow Doppler study of thethyroid was ordered. The radiologistthought that the flow looked “normal”.

•He who knows syphilis knowsmedicine

-Sir William Osler

•He who knows amiodarone knowsthe thyroid

-David Cooper

Amiodarone pharmacology

• 37% iodine by weight

• A drug dose of 600 mg/d yields 225 mgorganic iodine– This yields 22.5 mg iodine/day released

into the circulation

– Normal iodine intake in U.S. is 100-500mcg/ day

Amiodarone and the ThyroidMajor Considerations

• Release of large amount of iodine– Effects on iodine clearance, uptake

– Effects on T4 production

– Minimal effect in individuals with normal thyroid functionand no thyroid autoimmunity

• Block of T4 entry into cells

• Block of T4 to T3 conversion

• Inhibition of T3 binding to the thyroid hormonereceptor beta

– ?partially explains cardiac effects

Acute effect of amiodarone on thyroid function Iervasi et al. 1997

T4

T3

TSH

Acute effect of amiodarone on thyroid function

Melmed et al. 1981

Chronic effects of amiodarone on thyroid function

Trip et al. 1991

Thyroid Function in92 Amiodarone Treated Patients

Mean duration of therapy 10 monthsPosner et al. 1994

Hypothyroid12%

Euthyroid41%

HyperT4emic32%

Hyperthyroid3%

Subclin. Hypothyroidism

12%

Type 1 Amiodarone-inducedthyrotoxicosis (AIT type 1)

• underlying thyroid disease: multinodulargoiter or latent autoimmune disease

• High iodine load triggers excessivethyroid hormone synthesis and release(Jod-Basedow phenomenon)

• or provokes the development of Graves’disease

Type 2 Amiodarone inducedthyrotoxicosis (AIT-type 2)

• no apparent underlying thyroid disease

• Destructive inflammatory thyroiditisreleasing preformed thyroid hormoneinto the circulation

• Inflammation mediated by directcytotoxic effect of amiodarone and itsmetabolites on thyroid follicular epithelialcells

Changing Proportion of AIT Type 1 and Type 2Bogazzi et al. 2007

Amiodarone-inducedthyrotoxicosis: clinical

• Usual presentation: weight loss, weakness– Goiter may be absent

– Worsening rhythm disturbance

– Usually rapid onset

– Tachycardia may be masked

• PE:– AIT Type 1:Thyroid enlarged, nodular

– AIT Type 2: Thyroid nl. to sl. enlarged; rarelytender

Amiodarone-induced thyrotoxicosislaboratory features

• Classic: high T4, free T4, T3, low TSH– Caveat: T3 may not be elevated but 50-100%

above baseline

• Distinguishing Type 1 versus Type 2:– No difference in T4 or T3 between type 1 (iodide

induced) versus Type 2 (destructive)

– Radioiodine uptake of little help

– Interleukin-6 (IL-6) may or may not be helpful

– Doppler ultrasound pattern may be helpful

Differences between type 1 and Type 2 amiodarone-induced thyrotoxicosis: Bartalena et al 1995

P valueType 2Type 1

NS107113Cum.amio.dose(gm)

< 0.011247Thyroid volume(cc)

< 0.012451Duration oftherapy (mo)

< 0.01440176Mean IL-6

NS1.31.2Main freeT3

NS3.94.1Mean free T4

NS6364Mean age

*

*

Elevated, (at least iniodine deficient

areas)Normal or lowIL-6

Normal,Decreasedparenchymal blood

flow

Increasedparenchymal blood

flow

Color flow Doppler ofthyroid

Hi T4, T3 normal orhigh

Hi T4, T3 normal orhigh

Thyroid functiontests

Very LowLowRadioiodine uptake

Normal, minimallyenlarged

underlying thyroiddisease

(multinodular goiter,Graves’ disease)

Thyroid ultrasound

NoYesPre-existing thyroid

disease

AIT Type 2AIT Type 1Factor

Amiodarone-induced thyrotoxicosistherapy

• May be very difficult

• Discontinue drug if possible

– Long half-life (22-55 days in serum) and infat stores

• Theoretically, treatment depends onunderlying diagnosis (type 1 versus type 2)

• Many prior series are hard to interpretbecause of failure to distinguish the two types

Amiodarone-induced thyrotoxicosistreatment of iodine-induced disease (type 1)

• High doses of antithyroid drugsmay be needed and still may beineffective

• Addition of perchlorate (500-1000mg/d) may be of value: notavailable

• Lithium may be useful• Plasmapheresis• Surgery ultimately may be required

Treatment of AIT-Type 1

• Indications for surgery in AIT-type 1

–Poor response to therapy

–Discontrinuation of amiodarone notpossible

–Life-threatening arrhythmias

Amiodarone-induced thyrotoxicosistreatment of destructive thyroiditis (Type 2)

• Glucocorticoids mainstay of therapy– Prednisone 40 mg/d to begin– Taper slowly over months

• Relapses possible with tapering– Monitor urinary iodide excretion as guide

• May evolve into transienthypothyroidism with rare permanenthypothyroidism

Type II Amiodarone-Induced Thyrotoxicosis% Euthyroid after 30 Days of Prednisone

Bogazzi et al, 2007

0

10

20

30

40

50

60

70

80

% e

uth

yro

id

FT4 < 5, TV <12 FT4 <5 TV >12 FT4 >5 TV <12 FT4 >5 TV >12

Amiodarone-induced thyrotoxicosisrole of combined therapy

• Useful in patients whose underlying etiology isunclear (?mixed form) or who do not respond toone therapy

• ? For all patients with severe disease?– Tapazole 40 mg/d

– Prednisone 40 mg/d

• If there is rapid response (within 1-2 weeks):– Taper Tapazole to 30 mg/d and recheck thyroid

function tests.

– If still doing well, rapidly taper Tapazole

– Continue prednisone with slow taper over months

Baseline check TSH, fT4, T3, antiTPO Ab every 6 months check TSH

TSH ↓

T4, T3 normal or minimallyincreased

fT4 elevated, T3 elevated or

2x higher than baseline

Monitor closelyEvaluate to distinguish

AIT 1 From AIT 2

D/C amiodarone If at all possible

(? not in Type 2 AIT)

Treat appropriately

Management of Low TSH in Amiodarone-Treated Patients

BEWARE OF WARFARIN•Effects of amiodarone↑•Hyperthyroid Effects ↑

80 year old man• The patient was thought to have amiodarone-

related thyroiditis (Type II). He was started onPrednisone 40 mg/d as a single daily dose.

• One week later, the following laboratorystudies were obtained: free T4 2.8 ng/dl T3277 ng/dl (had been 3 ng/dl and 190 ng/dl)

• What now?

Amiodarone-induced thyrotoxicosisrole of combined therapy

• Useful in patients whose underlyingetiology is unclear– methimazole 40 mg/d

– Prednisone 40 mg/d

• If there is rapid response (within 1 week):– Taper methimazole to 30 mg/d and recheck

TFT’s

– If still doing well, rapidly taper methimazole

– Continue prednisone w. slow taper overmonths

80 year old man• The patient was started on methimazole 40 mg/d

and the prednisone was continued. One week later,fT4 2.9 ng/dl T3 282 ng/dl.

• Two weeks later the patient developed shortness ofbreath and was hospitalized with congestive heartfailure.

• Prednisone and methimazole were continued. Onthe third hospital day, the patient developed a feverto 103 F. A WBC, which had been normal onadmission, was 3000 mm3 with 10% granulocytes.Strep. Pneumoniae grew from the blood and CXRshowed a hazy infiltrate.

Antithyroid Drug-Induced Agranulocytosis

• Defined as granulocyte count <0.5 x 109/l

• Frequency 0.2-0.5% (one out of 200-500)

• Probably immune in etiology

• Usually within first 60 days of therapy

• Dose related with MMI, not PTU

• ?greater frequency in the elderly

• Monitoring not “standard of care” but maydetect agranulocytosis that is asymptomaticor incipient (Tajiri et al. 1990)

2008 Epub ahead of print

LATIN StudyHamerschlak et al. 2008

• Multinational case control study ofagranulocytosis

• 9 sites: 7 in Brazil, 1 in Buenos Aires,Argentina, 1 in Monterey, Mexico

• Prospective from Jan. 2002-Dec. 2005 (4 yr)

• Study workers searched for all cases ofagranulocytosis in their area: weekly contactwith hematologists, ID specialists, and primarycare physicians and monthly reports fromclinical laboratories in the area.

LATIN StudyHamerschlak et al. 2008

• Defined as: granulocyte count <500/mm3 andnormal hemoglobin and platelet count

• For each case, 4 controls were selected from thesame hospital or clinic where the patient had been

• 52 cases identified in 4 years

• Highest rates in the elderly

• 6/52 patients (11%) died

• Methmazole was the number 1 drug (27% of allcases)

• Buenos Aires: highest rate of any of the 9 sites

LATIN StudyIncidence of agranulocytosis according to age

LATIN StudyHamerschlak et al. 2008

LATIN StudyHamerschlak et al. 2008

LATIN StudyHamerschlak et al. 2008

Antithyroid Drug-Induced Agranulocytosis

• May be asymptomatic until infection develops

• Classic: fever, chills, fulmanent oropharyngealinfection

• Other: pneumonia, mouth ulcers, skin,anorectal infections (Sheng et al. 1999)

• Immediate drug discontinuation andhospitalization

• Bone marrow aspirate to predict recovery timeand response to G-CSF

• Broad spectrum antibiotics in febrile patients

• No evidence to support use of glucocorticoids

Antithyroid-drug-induced agranulocytosiscomplicated by life-threatening infections.

Sheng et al. 1999

• Of 5653 patients treated with ATD’s over 10 years,13 (0.23%) developed agranulocytosis with life-threatening infections.

• The most common presentations were fever (92%)and sore throat (85%)

• Initial clinical diagnoses were acute pharyngitis(46%), acute tonsillitis (38%), pneumonia (15%) andurinary tract infection (8%).

• Two patients died of uncontrolled infection, thyroidstorm and multiple organ failure.

Drug-Induced AgranulocytosisJulia et al. 1991, Ibanez et al. 2008

• Poor outcome in patients with advanced age,lower granulocyte counts, shock, bacteremia

• Use of G-CSF is recommended– but data suggest low efficacy in patients with severe

marrow hypoplasia

– In large series of drug-inducedagranulocytosis from a variety of drugs• Mean time to recovery w. GCSF 5 vs. 7 days

• Mortality rate 9% vs. 11% (P=NS)

Tamai et al. 1993Myeloid:Erythroid Ratio and Recovery Time with GCSF

RCT of G-CSF in ATD-Induced AgranulocytosisFukata et al. Thyroid 1999

2007

Tamai et al. 1993

Tamai et al. 1993

GCSF in ATD-induced agranulocytosis.Andres et al. 2001

• 20 patients (10 treated with G-CSF) with antithyroid-drug induced agranulocytosis.

• G-CSF (300 mcg/day subcutaneously) was usedwhere the neutrophil count was <0.1x109/l, or thepatient was aged >70 years, or there were severefeatures of infection or underlying disease.

• Clinical features included isolated fever (n=7),pneumonia (n=5), septicemia or septic shock (n=5)and acute tonsillitis (n=3).

GCSF in ATD-induced agranulocytosis.Andres et al. 2001

• Mean durations of:– hematological recovery

• 6.8+/-4 days vs. 11.6+/-5 days

– antibiotic therapy• 7.5+/-3.8 days vs. 12+/-4.5 days

– hospitalization• 7.3+/-4.8 days vs. 13+/-6.1 days

– All significantly reduced with G-CSF (all p<0.05).

• No patient died. GCSF reduced overall costs.

80 year old man• He was intubated and transferred to the ICU.

• Over the next week the WBC gradually normalized,the patient defervesced, and thyroid function testsbecame normal on continued prednisone therapy.

• He remained comatose and respirator dependent forthe next two weeks.

• Life-support was withdrawn at the urging of hisfamily, and he died shortly thereafter.

80 year old man• Lessons

– Amiodarone-induced thyrotoxicosis can be an verydifficult problem and calls for expert input

– Some patients may not respond to pharmacologicaltherapy and should proceed to surgery

– Antithyroid drug-induced agranulocytosis occurs ifyou treat enough patients, and is always a potentiallydevastating side-effect.

– It is more common in older patients and with higherdoses of methimazole

– G-CSF may shorten time to recovery but does notimprove survival

Case 2

A 16 year old girl

16 year old girl• Presented at age 14 with typical symptoms

of hyperthyroidism, including weight loss,insomnia, and declining school performance

• Seen by her pediatrician---- PE: tachycardic,proptosis, large goiter

• TFT’s c/w thyrotoxicosis, started onmethimazole 10 mg tid, atenolol 50 mg/d

Graves’ Disease in Adolescents• Presentation

– Peak frequency in teenagers (1:5000)

– Female predominance (3:1-7:1)

– Typical symptoms:

• wt loss, rapid heart rate, weakness,tremor

– Typical signs

• goiter (may be missed)

• eye findings mild but common, seen inolder children; rarely the initial complaint

• dermopathy very very rare in children

Sum of 3 seriesGraves’ disease in childhood

Graves’ Disease in Adolescents

Other Notable Features

• Acceleration of linear growth andadvancement of bone age

• Behavioral disturbances– decreased attention span, hyperactivity,

decreased sleep, poor school performance

• Puberty may be delayed

• Menstrual abnormalities and amenorrheacommon in girls

16 year old girl

• After 2 weeks, she developed a diffusepruritic rash

what would you do?

• switched to PTU 100 mg tid

• Over the next 6 months, TFT’simproved, but never normalized

• referred to a pediatric endocrinologist

16 year old girl

• He determined that compliance wassatisfactory

• increased PTU to 200 mg tid

• On this dose, fT4 remained normal, butserum T3 remained elevated

• referred for consideration of radioiodinetherapy

16 year old girl

TFT’s from 2 days earlier (on PTU):

fT4 0.3 ng/dl (0.8-1.8) TSH <0.005 mU/L

How do you interpret these tests?What others would you order?

T3 650 ng/dl ( 80-180)

Discordant Hypothyroxinemia andHypertriiodothyroninemia in treated patients withGraves’ disease Chen JS, Ladenson PW 1986

• 6 of 60 patients (10%) had discordance

• 4 on ATD’s; 2 after 131I

• TSH elevated in 2, low in 3, normal in 1

• Mechanism:– ?intrathyroidal iodine deficiency

– Increased intrathyroidal Type II deiodinase

– High TSH stimulates T3 production

• Lesson: low TSH, low fT4: measure T3

Radioiodine Therapy in Adolescents

• Usually used as alternate after antithyroiddrug failure

• First-line therapy in some centers

• Hypothyroidism “inevitable”: life-long F/U

• Generally effective with one dose

Radioiodine Therapy in Adolescents

• No evidence for infertility

• No evidence for birth defects

• No evidence for cancer or leukemia:– only 4 reported cases of thyroid cancer

• possible increase in thyroid adenomas(?seen with lower RAI doses)

• BUT: most studies are relatively small,with F/U periods in the 5-15 year range

Radioiodine Therapy in Adolescents:Birth Defects

Rivkees et al. 1999• No increased risk of birth defects in

offspring of individuals treated withradioiodine as children or adolescents:– 500 children born to 370 individuals treated

for hyperthyroidism (7 series)

– 77 children born to individuals receivingradioiodine for thyroid cancer

JCEM 2004

107/116 patients aged < 20 yr.Average F/U 36 years

･NO thyroid cancer orleukemia･NO incr. in congenitalanomalies/abortions

Surgery in Graves’ Disease in Adolescence

• No longer popular as first line therapy

• Preparation needed

• Total thyroidectomy, not subtotal

• recurrence rate: 3-15%

• complications (2000 children, 6 series):– hypocalcemia: transient (10%), permanent (2%)

– vocal cord paralysis (2%)

– temporary tracheostomy (0.7%)

– hemorrhage (0.2%)

– death (0.08%)

16 year old girl• Options, including surgery and

radioiodine discussed; pt. and motherboth preferred radioiodine

• PTU stopped for 3 days

• 24 hr. RAIU 65%

• 15 mCi 131I administered

• PTU not restarted; atenolol continued

• after 3 months:

• fT4 3.5 ng/dl (0.8-1.8) T3 445 ng/dl (80-180)

Effect of ATD Pretreatment on RAIOutcomes

Walter et al. 2007

16 year old girl• At this time, her orthopedic surgeon told

the patient that the pins needed to beremoved from the shoulder, requiringgeneral anesthesia

• What would you do now?

16 year old girl• The patient was restarted on PTU 100

mg tid• 2 weeks later, she developed malaise,

RUQ pain, and dark urine.• Seen by pediatrician: jaundiced, enlarged

tender liver• serum bilirubin: 12 mg/dl, transaminases

20x above normal• Serum ammonia, clotting times normal• Screens for hepatitis A, B, C all negative• What now?

Toxic Reactions to Antithyroid Drugs in Children

• Occur in 5-20% (same or more than adults)

• Summary of 500 children from 5 caseseries:

Rash (macular, papular,urticarial) 9%Granulocytopenia 4.5%

Arthritis 2.4%

Nausea 1.1%

Agranulocytosis 0.4%

Hepatitis 0.4%

Vasculitis,other rare

Antithyroid Drugs: Toxicity

PTU MMI

Minor Reactions (fever,

rash)

1-5% 1-5% (dose-related)

Agranulocytosis 0.2-0.5% (not dose -related)

0.2-0.5% (dose-related)

Hepatotoxicity Hepatitis (? 1%)

Cholestatic (few deaths)

Vasculitis ANCA + (very rare)

Teratogenesis NO Yes

Hepatotoxicity from PTU• Therapy: recognition and cessation of PTU• Expectant management of coma,

prolonged PT, hepatorenal syndrome• requires specialized care, including

possible transplant• No evidence that steroids help• * mild elev. LFT’s occur in 35% of untreated

pts.• *transaminases 1.1-6-fold above ULN

occur in 30% within 2 months of startingPTU

16 year old girl• PTU discontinued; LFT’s normalized over 2 wk

• SSKI 2 gtts tid started and atenolol increased to50 mg bid

• 10 days later, fT4 2.3 ng/dl T3 225 ng/dl

• Braverman LE, Woeber KA, Ingbar SH. Induction ofmyxedema by iodide in patients euthyroid afterradioiodine or surgical treatment of diffuse toxic goiter.N Engl J Med. 1969

16 year old girl• The patient underwent surgery uneventfully

• after 4 weeks, fT4 2.4 ng/dl T3 550 ng/dl

• a second dose of radioiodine (20 mCi) given

• 6 weeks later, fT4 0.6 ng/dl, T3 115 ng/dl

• 6 weeks after that, fT4 2.1 ng/dl, T3 350 ng/dl

• What now?

16 year old girl

• A third 20 mCi dose of radioiodine was given3 months later

• thyroxine was started 2 months after that

• the patient never had worsening of her eyedisease

• currently doing well in school with normalthyroid function on L-T4 0.125 mg/d

16 year old girlLessons

• Hyperthyroidism is difficult to treat(sometimes)

• beware of T3 toxicosis in patients withlow T4 and low TSH

• drug allergy may occur after priorbenign exposure and may be severe

• SSKI is useful in the acute setting

Muchas Gracias!