Learning Objectives Hypothyroidism What should be ... - Pri-Med

Learning Objectives

• Review clinical presentation, diagnosis, and management of hypothyroidism

• Review clinical presentation, diagnosis, and management of hyperthyroidism

• Review basic management of thyroid nodules

• Content: covers introductory to intermediate level of proficiency

Hypothyroidism

• Normal TSH range• Primary Hypothyroidism• Pregnancy• Subclinical Hypothyroidism• Treatment

Serum TSH Concentration (mU/L)2.5‐97.5 Centiles

Reference Population with Risk Factors ExcludedMen Women Total0.47 0.41 0.45 Lower Limit4.15 4.09 4.12 Upper Limit

Median1.40 1.37 1.39

TSH remained within the normal range with increasing decade of age

Hollowell et al, JCEM 87: 489, 2002

What should be considered the upper limit of the normal range of TSH values?

Recommendation 14.1

• If an age‐based upper limit of normal for a third generation TSH assay is not available in an iodine sufficient area, an upper limit of normal of 4.12 should be considered.

Garber et al, Thyroid 22: 1200, 2012

Thyroid Status, Disability, Cognitive Function and Survival in Old Age

• Prospective study of patients from age 85 to 89

• Elevated serum TSH levels were not associated with daily disability, depression, or cognitive impairment. Increasing TSH was associated with lower overall and cardiac mortality.

Gussekloo et al, JAMA 292: 2591, 2004.

TSH Distribution in disease‐free centenarians, Ashkenazi controls, and NHANES controls

Atzmon, G. et al. J Clin Endocrinol Metab 2009;94:1251-1254

Hypothyroidism

• Fatigue, cold intolerance• Constipation, difficulty concentrating• Bradycardia, hypothermia, slow speech, slow relaxation phase of reflexes.

• Children: Delayed growth and sexual maturation• Cardiac, pleural and peritoneal effusions.• Hypoglycemia, hypogonadism.

Causes of Thyroid Failure

• Autoimmune thyroiditis (Hashimoto’s) ‐most common• Thyroid ablation with radioactive iodine• Antithyroid drugs• Partial thyroidectomy• External beam radiation• Lithium therapy• Drugs containing iodine (e.g. amiodarone)• Silent, subacute, or postpartum thyroiditis

Primary Hypothyroidism• Radiation‐131‐I therapy, external irradiation (e.g. lymphoma, head and neck cancer)

• Thyroidectomy (lobectomy or total)• Infiltrative Diseases• Scleroderma‐About 10‐20% of patients have hypothyroidism• Sarcoidosis• Amyloidosis• Hemochromatosis• Riedel’s thyroiditis• Cancer metastatic to the thyroid gland

Primary Hypothyroidism• Nitroprusside• L‐asparaginase• Carbamazepine• Phenytoin• Sertraline• Ciprofloxacin• Rifampin• Ethionamide• Rituximab, Sunitinib, Motesanib, Axitinib, Pazopanib, Lenvatinib, Vandetanib, Cabozantinib, Sorafenib; PD1 and CTLA4 inhibitors.

Primary HypothyroidismTSH Receptor Mutation

• 10/88 children and adolescents with subclinical hypothyroidism had a mutation in the TSH receptor. These patients tended to have a family history of hypothyroidism.

Rapa et al., JCEM 94: 241, 09.

Causes of Elevated TSHPatients Usually Euthyroid

• Nonthyroidal illness• Pulsatile secretion• Heterophilic TSH or TSH receptor antibodies• T3/T4 antibodies• TSH secreting pituitary tumor (Hyperthyroid)• Resistance to T3/T4• Resistance to TSH

Hypothyroidism and Pregnancy

• Allan et al. (J Med Screening 7: 127, 2000) showed that fetal deaths correlated with TSH levels. If TSH greater than 6 mU/l, fetal death rate increased 4 fold.

• In 6 studies (4,123 women), the miscarriage rate was 23% in antibody positive women vs 8% if antibody was negative.

Hypothyroidism and Pregnancy

• Pregnancies in women with subclinical hypothyroidism were three times more likely to be complicated by placental abruption.

• The frequency of preterm delivery (before 34 weeks of gestation) was almost 2 fold higher in women with subclinical hypothyroidism.

Casey et al, Obstet Gynecol 195: 239, 2005.

Hypothyroidism and Pregnancy• 62 hypothyroid pregnant women compared to control group• Mean TSH 13 mU/l • No difference in birth weight or Apgar• IQ was 7 points lower (p<.005) for children (ages 7‐9) of mothers with untreated hypothyroidism (n=48).

• If mother was treated with LT4, the child’s IQ was the same as control (n=14).

• Problems: Small numbers, maternal TSH measured once, mothers and children not examined until children about age 7, unknown what TSH was throughout pregnancy.

Haddow et al, NEJM 341: 549, 1999.

Thyroid Hormone Early Adjustment in Pregnancy Trial (THERAPY TRIAL)

Yassa, et al., JCEM 95: 3234, 2010

• 60 women with treated hypothyroidism.

• Once pregnant, randomized to increase LT4 by either increasing their dosage by either 2 tablets/wk (29%) (Group A), or 3 tablets/wk (43%) (Group B). Thyroid function was tested biweekly through mid‐pregnancy, and at 30 weeks gestation.

Thyroid Hormone Early Adjustment in Pregnancy Trial (THERAPY TRIAL)

Yassa, et al., JCEM 95: 3234, 2010

Conclusions• A 2 tablet increase in levothyroxine initiated at confirmation of pregnancy prevents maternal hypothyroidism during the first trimester and mimics normal physiology.

• Monitoring TSH every 4 weeks through mid‐gestation is recommended.

ATA GuidelinesStagnaro‐Green et al, Thyroid 21: 1081, 2011

• Serum TSH values should be obtained early in pregnancy in the following women at high risk for overt hypothyroidism:

–History of thyroid dysfunction or prior thyroid surgery–Age > 30–Symptoms of thyroid dysfunction or goiter–TPO Ab positivity–Type 1 diabetes or other autoimmune disorders–History of miscarriage or preterm delivery–History of head or neck irradiation

ATA GuidelinesStagnaro‐Green et al, Thyroid 21: 1081, 2011

• Serum TSH values should be obtained early in pregnancy in the following women at high risk for overt hypothyroidism:

–Family history of thyroid dysfunction–Morbid obesity (BMI >/= 40 k/m2)–Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast–Infertility–Residing in an area of known moderate to severe iodine insufficiency

Clinical Practice Guidelines for Hypothyroidism in AdultsGarber, et al. Thyroid 22: 1200, 2012

RECOMMENDATION 9• In pregnancy, measure TSH and free T4

RECOMMENDATION 14.2• If trimester‐specific reference ranges for TSH are not available in the laboratory,

use the following ranges:– first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; third trimester, 3.5 mIU/L.

RECOMMENDATION 25.3• Maternal serum TSH (and total T4) should be monitored every 4 weeks during the

first half of pregnancy and at least once between 26 and 32 weeks gestation

Treatment of Hypothyroidism

RECOMMENDATION 22.1• Patients with hypothyroidism should be treated with L‐thyroxine monotherapy.

RECOMMENDATION 22.2• The evidence does not support using L‐thyroxine and L‐triiodothyronine combinations to treat hypothyroidism

Garber, et al. Thyroid 22: 1200, 2012

Treatment of Subclinical Hypothyroidism

RECOMMENDATION 15• TSH levels > 10 mIU/L are associated with an increased risk for heart failure and cardiovascular mortality, and should be considered for treatment with L‐thyroxine.

Garber, et al. Thyroid 22: 1200, 2012

Hyperthyroidism

• Overt hyperthyroidism – Clinical Features– Diagnosis/ differential diagnosis– Therapy

• Orbitopathy• Hyperthyroidism in pregnancy• Subclinical hyperthyroidism

Thyrotoxicosis: Clinical Features

Symptom % PatientsFatigue 69%Weight loss 61%Heat intolerance 55%Palpitations 54%Tremulousness 54%Nervousness/ anxiety 47%Diaphoresis 45%Increased appetite 42%Hyperdefecation 22%Neck fullness 22%Eye symptoms 11%Dyspnea 10%Weight gain 8%

Elderly-may present with only weight loss, dyspnea, CHF, atrial fibrillationData derived from:•BoelaertK, et al J Clin Endocrinol Metab 2010; 95:2715.•NordykeRA et al Ann Intern Med 1988; 148:626;

Burch HB from Werner’s The Thyroid 10thEdition, 2012.

Sign % PatientsTachycardia (regular) 80%Palpable goiter 75%Eye signs 50%Tremor 48%Moist skin 34%Atrial fibrillation 4%

Causes of Thyrotoxicosis

Common causesGraves’ diseaseToxic MNGSolitary “hot” noduleSubacute thyroiditisPostpartum thyroiditisExogenous

Rare causesTSH-secreting pituitary adenomahCG-producing cancerMetastatic thyroid cancer

Drug-induced–Interferon–IL-2–Tyrosine kinase inhibitors–Amiodarone–LithiumStruma ovarii

Traditional testing in Suspected Thyrotoxicosis

Ross DS, et al. Thyroid. 2016 Oct;26(10):1343-1421.

Are Radioactive Iodine Uptake and Scan Really Needed in Classic Graves’ Disease

2016 ATA Hyperthyroidism GuidelinesRecommendation 1: • If the diagnosis is not apparent clinically, diagnostic studies can include:

• (1)TRAb measurement• (2)Radioactive iodine uptake (RAIU)• (3)Measurement of thyroid blood flow by Doppler

Strong recommendation, moderate-quality evidenceRoss DS, et al. Thyroid. 2016 Oct;26(10):1343-1421.

Traditional testing in Suspected Thyrotoxicosis


Testing Strategy in Suspected Thyrotoxicosis


















Treatment Options in Hyperthyroidism

• Antithyroid drugs• Radioiodine• Thyroidectomy

Methimazole Dosing

Degree Free T4 fold increase Starting doseMild 1to 1.5 x ULN 5-10 mg dailyModerate 1.5 to 2 x ULN 10-20 mg dailySevere 2 to 3x ULN 30-40 mg daily

Ross DS, et al. Thyroid. 2016 Oct;26(10):1343-1421

Antithyroid Drug Adverse Effects

MINORCommon (1‐5%)‐ Rash‐ Urticaria‐ Arthralgia‐ Transaminasemia‐ Transient leukopenia

Rare (0.2‐0.5%)‐ Arthritis

MAJORRare (0.2‐0.5%)‐Agranulocytosis

Very Rare‐Aplastic anemia‐Hepatitis (PTU)‐Cholestasis(MMI)‐Vasculitis/ lupus‐Hypoglycemia

Cooper DS. The Thyroid, Ninth Edition, 2005; p 671.

2016 American Thyroid Association Guidelines

Recommendation 13: Methimazole should be used in virtually every patient who chooses antithyroid drug therapy for Graves’ disease, except:

1.During the first trimester of pregnancy

2.In the treatment of thyroid storm

3.In patients with reactions to MMI who refuse radioactive iodine therapy or surgery

Ross DS, et al. Thyroid. 2016 Oct;26(10):1343-1421

2016 American Thyroid Association Guidelines

RECOMMENDATION 8

Sufficient activity of RAI should be administered in a single application, typically a mean dose of 10–15 mCi (370-555 MBq), to render the patient hypothyroid.

Strong recommendation, moderate-quality evidence

Ross DS, et al. Thyroid. 2016 Oct;26(10):1343-1421Ross DS, et al. Thyroid. 2016 Oct;26(10):1343-1421

Surgical Indications in Graves’ Disease

• Cold nodules/ suspicious nodules• Patient preference• Severe orbitopathy?• Patients desiring pregnancy in < 6 months


Clinical Factors that Favor a Treatment Modality

• Antithyroid Drugs– Patients with a higher chance of remission (mild disease, small goiter)– Patients with moderate‐to‐severe Graves’ Orbitopathy

• Radioiodine– Elderly and other patients who are poor surgical candidates (comorbidities, prior neck surgery or irradiation)

• Surgery– When concurrent thyroid malignancy is suspected– Patients with symptomatic compression from large goiters– Women planning a pregnancy within the next 6 months (avoidance of 131I)


American Thyroid Association Guidelines 2016: Patient Values that Favor a Treatment Modality

Modality Higher Value Lower ValueATD Avoid life‐long LT4

Avoid 131‐IAvoiding risk surgery

Adverse drug effectsDuration of therapy

131‐I Definitive therapyAvoiding risk surgery

Radiation exposureNeed for lifelong LT4Risk of n/w GO

Surgery Rapid resolution Risk of surgeryNeed for lifelong LT4


Pregnancy and Thyrotoxicosis: Complications from Poorly Controlled Thyrotoxicosis

Maternal FetalPreeclampsia ThyrotoxicosisCongestive heart failure Growth retardationThyroid storm Risk of surgery

Need for lifelong LT4Miscarriage PrematurityPlacenta abruption Stillbirth

MestmanJ. Curr Opin Endocrinol Diabetes Obes 2012; 19:394–401

Treatment Principles in Pregnancy

• Radioiodine contraindicated

• Use lowest effective dose of antithyroid drugs–Goal is slightly suppressed TSH, high normal free T4–Avoid fetal hypothyroidism & goiter–Dose requirements decrease during 2nd/3rd trimester


2016 American Thyroid Association Guidelines: Switching Antithyroid Drugs in Pregnancy


Subclinical Hyperthyroidism: Causes

• Iatrogenic• Graves’ disease • Toxic multinodular goiter• Thyroiditis• Subacute thyroiditis• Postpartum thyroiditis• Drug‐induced• Autonomously functioning thyroid nodule

Differential Diagnosis of a Suppressed TSH

• Overt T3‐thyrotoxicosis• Central hypothyroidism• Nonthyroidal illness• Drug effect• Corticosteroid• Dopamine• Octreotide

Is It Persistent? Follow‐Up of Abnormal TSH values

Normal Sl. High(5.5-10 mIU/L)

High(>10 mIU/L)

Low(<0.35 mIU/L)

Normal 98.0 1.4 0.1 0.6

Sl. High (5.5‐10 mIU/L)

62.1 34.6 2.9 0.3

High (> 10 mIU/L)

27.7 36.5 35.4 0.3

Low (<0.35 mIU/L)

51.5 1.2 0.6 46.7

MeyerovichJ, et al. Arch Intern Med 2007; 167:1533.

The Natural History of Subclinical Hyperthyroidism

Adapted from Cooper DS, BiondiB. Lancet; published online 23 Jan 2012

Consequences of Subclinical Hyperthyroidism

• Atrial fibrillation• Increased CV and all cause mortality• Osteoporosis/fracture

Atrial Fibrillation in Subclinical Hyperthyroidism

Sawinet al. N EnglJ Med 1994; 331:1249-1252.

Atrial Fibrillation in Subclinical Hyperthyroidism

Cappola AR et al. JAMA 2006; 295(9):1033-41.

2 fold increase

Cardiovascular Mortality in Subclinical Hyperthyroidism: Summary of Meta‐Analyses

Ochs et al. Ann Intern Med 2008; 148:832-45.Volzke et al. JCEM 2007 92: 2421-9.Singh et al. Int J Cardiol 2008; 125: 41-8.Collet et al. Arch Intern Med 2012:799-809.

All Cause Mortality in Subclinical Hyperthyroidism: Summary of Meta‐Analyses

Ochs et al. Ann Intern Med 2008; 148:832-45.Volzke et al. JCEM 2007 92: 2421-9.Singh et al. Int J Cardiol 2008; 125: 41-8.Collet et al. Arch Intern Med 2012:799-809.

Subclinical Hyperthyroidism and Fracture

• Prospective study: 9,704 white women > 65 • Followed for new hip or vertebral fractures• Stratified according to baseline TSH • Subset analysis: 148 hip fractures, 149 spine fractures, 398 controls

Bauer et al. Ann Intern Med 2001;134:561.


Bauer et al. Ann Intern Med 2001;134:561.


Subclinical Hyperthyroidism and Fracture Subclinical Hyperthyroidism and Fracture

Blum et al. JAMA 2015; 313:2055.

Lowest TSH have highest association w/ fracture

When Does Subclinical Hyperthyroidism Require Therapy?










When to Treat Subclinical Hyperthyroidism

Mai VQ, Burch HB Endocrine Practice 2012

When to Treat Subclinical Hyperthyroidism

Mai VQ, Burch HB Endocrine Practice 2012

Summary: Subclinical Hyperthyroidism

• Occurs in 1‐2% of U.S. general population• Associated with atrial dysrhythmia, increased cardiovascular mortality, and fractures

• Some patients resolve spontaneously but most patients require therapy

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Learning Objectives Hypothyroidism What should be ... - Pri-Med