Hypothyroidism Update 2020 · §Discuss management strategies for patients who have persistent symptoms while on biochemically adequate treatment. Hypothyroidism Update 2020 Learning

HypothyroidismUpdate

2020

Michael T. McDermott MDDirector, Endocrinology and Diabetes Practice

University of Colorado Hospital

Disclosures

§ Michael T. McDermott MD is on an Advisory Board

for Novo Nordisk.

§ Any unlabeled/unapproved uses of drugs or

products referenced will be disclosed.

§ Explain the diagnostic tests for primary and central

hypothyroidism.

§ Discuss the clinical significance of overt and subclinical

hypothyroidism.

§ Review the management recommendations for hypothyroidism.

§ Discuss management strategies for patients who have persistent

symptoms while on biochemically adequate treatment.

Hypothyroidism Update 2020Learning Objectives

TRH

T3 + T4

Hypothalamus

TSH

Thyroid Hormone Regulation

T36 ug/d

T320 ug/d

T4101 ug/d

T326 ug/d

Pilo A, Am J Physiol 1990; 258:E715-26

Secretion Ratio T4:T3 = 14:1

Thyroid Hormone Production

D1

Screening / Case Finding

i TSH h TSH

TSH

Free T4Total T3

Free T4

Hyperthyroidism Hypothyroidism

Thyroid Function Testing

McDermott MT. Ann Intern Med 2009; 151 (11):ITC61McDermott MT. Ann Intern Med 2012; 157:ITC-1-14.

h TRH

Hypothalamus

h TSH

i T3 + i T4

h TSHFree T4 Low

h TSHFree T4 Normal

Overt

Primary Hypothyroidism

Subclinical

Mild Hypothyroidism

i TRH

Hypothalamus

i TSH

i T3 + i T4

TSH Low/NormalFree T4 Low

Central (Secondary) Hypothyroidism

HypothyroidismClinical Features

Symptom Frequency (1997)Dry Skin 76%Cold Intolerance 64%Coarse Skin 60%Puffy Eyelids 60%Weight Gain 54%Symptom Frequency (2014)Fatigue 81%Dry Skin 63%Shortness of Breath 51%

Zulewski H. J Clin Endocrinol Metab 1997; 82:771-776Carlé A. Eur J Endocrinol 2014;171:593-602

Number of hypothyroidism-associated symptoms reported by hypothyroid patients at disease onset and by their region-, age- and sex-matched controls

Carlé A. Eur J Endocrinol 2014;171:593-602

Thyroid Related Symptoms Common in Euthyroid Subjects

A 33 year old woman complains of fatigue and weight gain of 15 lbover the past 6 months. PMH: Type 1 Diabetes Mellitus Meds: Insulin Pump TherapyPE: BP 134/80 P 64 Ht 5’6’’ Wt 154 lb. (70 kg)Thyroid: firm, granular thyroid Eyes: periorbital edema Reflexes: delayed reflex relaxation

Lab: TSH 112 mU/L (nl: 0.45-4.5) Free T4 0.3 ng/ml (nl: 0.8-1.8)TPO antibodies 72.5 units (nl < 0.3)

Case 1

Which of the following to you recommend as starting therapy?A. Levothyroxine 112 mcg daily (1.6 mcg/kg)B. Levothyroxine 50 mcg dailyC. Levothyroxine 100 mcg daily plus Liothyronine 5 mcg BIDD. Desiccated thyroid extract 60 mg daily

Answer: A. Levothyroxine 112 mcg daily (1.6 mcg/kg)

Case 1

Levothyroxine (LT4) is the hypothyroidism treatment of choice; it effectively and safely relieves symptoms and normalizes laboratory tests in the majority of patients.

After absorption in the duodenum, circulating LT4 is converted to T3 by peripheral tissue deiodinases at a rate that is regulated by the metabolic needs of each organ and tissue. The long serum half-life of LT4 (5 days) yields stable TSH, T4, and T3 levels.

Average LT4 replacement dose in healthy adults with overt hypothyroidism: 1.6 mcg/kg/day. Lean body mass [approximate body weight that would yield a body mass index (BMI) of 24-25 kg/m2 for the individual’s height] is a better predictor of dose requirements than total body weight.

Jonklaas J, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid 2014; 24:1670-751.McDermott MT. In The Clinic: Hypothyroidism. Ann Intern Med 2020; (in press)

Primary HypothyroidismEtiology

Lymphocytic Thyroiditis (Hashimoto’s Thyroiditis)

ThyroidectomyI-131 AblationMedications:

§ Lithium§ Amiodarone§ Alpha Interferon§ Multi-Kinase Inhibitors § Immune Checkpoint Inhibitors

§ Levothyroxine: 1.6 mcg/kg QD

§ TSH Recheck: 6 Weeks

§ Dose Titration: TSH in Reference Range

Age < 60 Years and No CAD

Overt HypothyroidismTreatment

Jonklass J. Thyroid 2014; 24: 1670-1751 McDermott M. Ann Intern Med 2020; XX: ITC (in press)

Jonklass J, Thyroid 2014; 24: 1670-1751

Hypothyroidism GuidelinesATA 2014

Efficacy in resolving hypothyroid symptomsLong-term experience of its benefitsFavorable side effect profileGood intestinal absorptionEase of administrationLong serum half-lifeLow cost

Levothyroxine is Recommended as the Treatment of Choice

§ Take dose 1 hour before or 4 hours after a meal

§ Separate at least 4 hours from iron, calcium and soy

§ If you miss

§ One dose: take 2 pills the next day

§ Two doses: take 2 pills a day the next 2 days

McDermott M. Ann Intern Med 2020; XX: ITC (in press)

Levothyroxine Dosing Instructions

HO O CH2

NH2

C

H

I

C OH

OI

I

I

Thyroxine Structure

HO O CH2

NH2

C

H

I

C O-

OI

I

I

Levothyroxine Sodium

Na+

Optimal TSH Goal: 0.5-2.0 mU/L ?

Not Validated by Evidence

TSH Distribution in Normal Population

TSH Variation Within and Above Normal RangeEffect on Symptoms in Hypothyroid Subjects

Samuels MH. Effects of altering levothyroxine (LT4) doses on quality of life, mood and cognition in LT4 treated patients. J Clin Endocrinol Metab 2018; 103:1997-2008.

138 Patients: Hypothyroidism on LT4 Replacement

RCT: TSH Target Low Nl, High Nl or Slightly High x 6 months

Outcomes: Health Survey (SF-36), Quality of Life, Mood,

Cognition

TSH Variation Within and Above Normal RangeEffect on Symptoms in Hypothyroid Subjects

Outcomes - No Difference Among the 3 Groups

General Health (SF-36) Thyroid Related Quality of Life

Mood Cognition

138 Patients (RCT 6 Mos): Hypothyroidism on LT4 Replacement

Group (TSH) Low Nl High Nl Slightly High P

TSH Level (mU/L) 1.85 3.93 9.49 < .001

LT4 Dose (ug/kg) 1.50 1.32 0.78 < .001

Samuels MH. Effects of altering levothyroxine (LT4) doses on quality of life, mood and cognition in LT4 treated patients. J Clin Endocrinol Metab 2018; 103:1997-2008.

Evidence does not support targeting specific

TSH values within the normal reference range

Hypothyroidism Treatment GuidelinesATA/AACE 2012 and ATA 2014

Garber J, Endocr Pract 2012; 18:988-1028Jonklass J, Thyroid 2014; 24: 1670-1751

Optimal TSH Goal

This includes the following types of patients:Obese, Depressed, Athyreotic

A 72 year old woman complains of fatigue, mild depression andpoor memory that have been progressive over 3 years span.PMH: DJD, GERD Meds: ASA, H2 BlockerPE: BP 150/86 P 80 Ht 5’9” Wt 172 lb. (78 kg) Exam: normalLab: TSH 43.6 mU/L (nl: 0.45-4.5) Free T4 0.5 ng/dl (nl: 0.8-1.8)

Chol 255 TG 165 HDL 45 LDL 177

Case 2

Which of the following to you recommend as starting therapy?A. Levothyroxine 112 mcg daily (1.6 mcg/kg)B. Levothyroxine 50 mcg dailyC. Levothyroxine 100 mcg daily plus Liothyronine 5 mcg BIDD. Desiccated thyroid extract 60 mg daily

Answer: B. Levothyroxine 50 mcg daily

Case 2

Levothyroxine (LT4) is the hypothyroidism treatment of choice; it effectively and safely relieves symptoms and normalizes laboratory tests in the majority of patients.

After absorption in the duodenum, circulating LT4 is converted to T3 by peripheral tissue deiodinases at a rate that is regulated by the metabolic needs of each organ and tissue. The long serum half-life (5 days) of LT4 yields stable TSH, T4, and T3 levels.

Patients > 60 years old or with known CAD: start on low LT4 dose (25-50 mcg/day) with dose titrations of 12.5-25 mcg/day every 6-8 weeks until the goal TSH level is reached. “Start low, go slow” approach is recommended to prevent the development of dysrhythmias or ischemic events when full replacement doses are abruptly started or when the dose is increased too rapidly.

Jonklaas J, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid 2014; 24:1670-751.McDermott MT. In The Clinic: Hypothyroidism. Ann Intern Med 2020; (in press)

Age > 60 Years or CAD

Jonklass J. Thyroid 2014; 24: 1670-1751 McDermott M. Ann Intern Med 2020; XX: ITC (in press)

§ Levothyroxine: 25-50 mcg QD



§ Age > 70: 4.0 < TSH < 6.0 mU/L

Overt HypothyroidismTreatment

Surks MI, J Clin Endocrinol Metab 2007; 92:4575-82

TSH Distribution Changes with Age

Hypothyroidism Treatment GuidelinesATA/AACE 2012 and ATA 2014

TSH Goals in the Elderly

Garber J, Endocr Pract 2012; 18:988-1028Jonklass J, Thyroid 2014; 24: 1670-1751

Based on the current evidence, it is reasonable to raise the target TSH to 4 – 6 mU/L in persons

greater than age 70 – 80 years

A 76 year old man complains of recent fatigue, weight gain anddecreased memory for current events.PMH: DM2, HTN Meds: Metformin, LisinoprilPE: BP 138/77 P 78 Ht 6’1” Wt 188 lb. (85 kg) Exam: normalLab: TSH 9.6 mU/L (nl: 0.45-4.5) Free T4 0.9 ng/dl (nl: 0.8-1.8)

Chol 212 TG 121 HDL 56 LDL 132

Case 3

Which of the following statements is true?A. Levothyroxine treatment will improve his symptomsB. Levothyroxine treatment will lower his LDL cholesterolC. Levothyroxine treatment will lower his CVD riskD. Levothyroxine treatment will reduce his mortality risk

Answer: B. Levothyroxine treatment will lower his LDL cholesterol

Case 3

LT4 treatment lowers LDL cholesterol levels in patients with subclinical hypothyroidism (SCH).

Patients with mild SCH do not experience symptom improvement with LT4 therapy if at baseline they have minimal symptoms and only slight TSH elevations. Two recent RCTs in elderly subjects > age 65 years and > age 80 years reported that LT4 treatment of mild SCH conferred no benefit for thyroid symptoms or fatigue and yielded secondary outcome improvement (BP, weight, waist circumference, grip strength). Treatment may benefit patients with more prominent baseline symptoms and when serum TSH levels are > 10 mU/L. Prospective, adequately powered RCTs have not yet been conducted to address whether LT4 treatment of SCH reduces the increased risk of CAD events and mortality that has been identified in the younger population. One cohort study reported a CVD benefit from LT4 treatment in younger patients but not in elderly subjects. Another study found that LT4 treatment of elderly subjects with SCH may even be associated with increased mortality.

References: next slide

Answer: B. Levothyroxine treatment will lower his LDL cholesterol

Case 3

McDermott MT. In The Clinic: Hypothyroidism. Ann Intern Med 2020; (in press). Peeters RP. Subclinical hypothyroidism. N Engl J Med 2017; 376:2556-65.Stott DJ. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med 2017; 376:2534-44.Mooijaart SP. Association between levothyroxine treatment and thyroid related symptoms among adults aged 80 years and older with subclinical hypothyroidism. JAMA. 2019 Oct 30:1-11. doi: 10.1001/jama.2019.17274. [Epub ahead of print]Razvi S. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med 2012; 172:811-7. Grossman A. Treatment with levothyroxine in subclinical hypothyroidism is associated with increased mortality in the elderly. Eur J Intern Med 2018; 50:65-68.

SubclinicalHypothyroidism

.01 0.45 4.5 10.0TSH mU/L

Free T4 ng/dl0.8 1.8

Mild Hypothyroidism

Subclinical HypothyroidismTreatment in Elderly Patients: TRUST Study

Subclinical Hypothyroidism: 737 Subjects > Age 65 TSH: 4.99-19.99 mU/L Free T4: in Reference RangeRCT: LT4 Rx (N=368) vs Placebo (N=369) x 1 Year

Primary Outcomes Hypothyroid Symptoms ScoreTiredness Score (Thyroid Related QOL Questionnaire)

Stott DJ. N Engl J Med 2017; 376:2534-44




Primary Outcome (1 Year) LT4 Placebo P

Hypothyroid Symptoms Score 16.6+16.9 16.7+17.5 0.99

Tiredness Score 28.7+20.2 28.6+19.5 0.40

Secondary Outcomes PBlood Pressure NSBody Mass Index NSWaist Circumference NSGrip Strength NSHyperthyroid Symptoms NS


Razvi S, J Clin Endocrinol Metab 2008; 93:2998-3007

Patients < 65 yrCVM Increased

Patients > 65 yrNo Increase CVM

Meta-Analysis (N = 15): 2,531 SCH Patients; 26,491 ControlsGroup 1: Included Patients < 65 years; Group 2: Only Patients > 65 years

Age < 65 vs > 65

Subclinical HypothyroidismCVD Mortality

4.5 10.0TSH mU/L

Subclinical HypothyroidismTreatment Recommendations

Clinical JudgmentRx Based on Symptoms

TreatmentRecommended

Age > 65: Controversy if Treatment Beneficial

Pregnant Women: Treat All to Trimester Specific Goals

Jonklass J, Thyroid 2014; 24: 1670-1751McDermott M. Ann Intern Med 2020; XX: ITC (in press)

Subclinical HypothyroidismTreatment

§ Levothyroxine: 25-50 mcg QD



§ Age > 70: 4.0 < TSH < 6.0 mU/L


Reason for Dissatisfaction

Fatigue / Low Energy 75%

Body Weight Issues 70%

Memory Problems 55%

Mood Problems 45%

Other 35%

Satisfaction with Rx – Visual Analog (VA) Scale (1-10): 5 (mean)ATA Survey: 12,000 Respondents (95% Women)

Peterson SJ. Thyroid 2018;28:707-721

Persistent Symptoms on LT4 Therapy

Satisfaction with Doctor - VA Scale (1-10): 5-6 (mean)

Doctor Knowledgeable - VA Scale (1-10): 5-6 (mean)

How Often Have You Changed Doctors1-4 Times 45%5-10 Times 10%

Peterson SJ. Thyroid 2018;28:707-721

Persistent Symptoms on LT4 Therapy

Peterson S, McAninch E, Bianco A. J Clin Endocrinol Metab 2016; 101:4964-73

LT4 Patients Controls

(469) (469) P-Value

TSH (mU/L) 2.13 2.15 0.83

Free T3 (pg/ml) 2.85 3.01 < 0.001

Free T4 (ng/ml) 0.94 0.80 < 0.001FT3/FT4 Ratio 3.18 3.85 < 0.001

NHANES Survey

HypothyroidismAltered Circulating T3 / T4 Ratio on LT4 Therapy

LT4 Patients Controls

(469) (469) P-Value

BMI 29.8 28.2 < 0.001

Kcal Consumption 1761 1759 0.98

Physical Activity 41% 32% < 0.01Anti-Depressant Use 22% 15% < 0.01

Peterson S, McAninch E, Bianco A. J Clin Endocrinol Metab 2016; 101:4964-73

HypothyroidismAltered Circulating T3 / T4 Ratio on LT4 Therapy

552 Subjects GenotypedD2: Thr92Ala Homozygotes = 16%Thr92Ala: D2 instability loop related to ubiquitination

General Health Questionnaire: Thr92Ala HomozygotesBaseline: Worse GHQ (p = 0.03)

Panicker V, J Clin Endocrinol Metab 2009; 94:1623-9

LT4 / LT3 TherapySubjects: 697 Gender: 84%W Age: 18-75 Dx: HypothyroidDesign: RCT Double Blind x 52 WeeksDosing: (Usual LT4 – 50 ug) + LT4 50 ug

(Usual LT4 – 50 ug) + LT3 10 ug

General Health Questionnaire: Thr92Ala HomozygotesLT4/LT3 c/w LT4 Rx: Improved GHQ (p = 0.03)


Hypothyroidism Treatment GuidelinesATA 2014

No consistently strong evidence of superiority of LT4/LT3 combination therapy over LT4 alone.

Recommend against routine use of combination LT4/LT3 therapy.

Combination LT4/LT3 Therapy


Hypothyroidism Treatment GuidelinesATA 2014

Potential Safety Concerns of DTE:1. Supraphysiologic serum T3 levels.

2. Paucity of long-term safety outcome data.

Recommend against routine use of combination DTE therapy.

Desiccated Thyroid Extract Therapy


Combination LT4/LT3 Therapy

Desiccated Thyroid Extract Therapy

§ Some patients prefer combined LT4/LT3 or DTE

§ Reasonable to use in patients with persistent symptoms if

done safely (maintain TSH in reference range)

§ Optimal T4:T3 Ratio: 14:1 – 10:1

Hypothyroidism TreatmentPatients with Persistent Symptoms on LT4 Therapy

§ Lifestyle Measures (Sleep, Exercise, Diet, i Stress)

§ Medical Illness / Depression Management

§ Regular Follow-up and Support

§ May Consider Combination T4/T3 or DTE

§ Levothyroxine (T4) + Liothyronine (T3) (10:1 ratio)

§ Desiccated Thyroid Extract (Porcine Thyroid)

§ Maintain TSH within Reference Range

Hypothyroidism TreatmentPatients with Persistent Symptoms on LT4 Therapy

Ott J, Thyroid 2011; 21:161-7

426 Euthyroid Women with Goiter: Thyroidectomy

TPO Ab Pos TPO Ab Neg P

TSH mU/L 1.7 1.5 NS

Symptom 6.7 + 2.5* 4.1 + 2.8 < .001Score

Symptoms Associated with TPO AntibodiesFatigue, Irritability, Nervousness, Dry Hair,

Lower Quality of Life

Chronic Lymphocytic ThyroiditisAre Some Symptoms Independent of Thyroid Hormone Levels?

Guldvog I. Ann Intern Med 2019; 170:453-64

150 Patients with Hashimoto’s Thyroiditis (age: 18-79 years):

persistent symptoms, euthyroid on thyroid hormone replacement

therapy with serum anti-TPO titers > 1000 IU/ml.

RCT: Thyroidectomy vs Thyroid Hormone Therapy x 18 months

Primary Outcome: General Health Score (SF-36) at 18 monthsSecondary Outcomes: Adverse Surgery Affects, 7 SF-36 sub-

scores, fatigue scores, anti-TPO titers (6, 12, 18 months)

Thyroidectomy for Hashimoto’s Thyroiditis

Serum Anti-TPO Antibody Titer


Individual Data

Mean Data



Surgery Medical Rx

Before After (1 yr) After (1 yr) P

General Health (SF36) 38 64 37 < 0.001

Fatigue Score 23 15 23 < 0.001

Chronic Fatigue (%) 83 33 73 < 0.001


§ TSH - best test to detect hypothyroidism

§ Hashimoto’s Thyroiditis is the most common cause

§ Treat hypothyroidism with LT4 to normalize TSH

§ TSH goal for elderly can be 4.0-6.0 mU/L

§ Mild hypothyroidism increases CVD risk/mortality in

patients < 65 years old but not > 65 years old

§ Treatment of patients with persistent symptoms

requires an individualized approach

Hypothyroidism Update 2020Summary

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Hypothyroidism Update 2020 · §Discuss management strategies for patients who have persistent symptoms while on biochemically adequate treatment. Hypothyroidism Update 2020 Learning