Management of Hypothyroidism, A Brief Review and Recent

AdvancesK.M. Mohamed Shakir, MD MACP MACE, FRCP, FACN, ECNU

Professor of MedicineUniformed Services University of the Health Sciences

&Consultant Endocrinologist at

Walter Reed National Military Medical CenterBethesda, Maryland USA

Primary hypothyroidism• Most common endocrine disease• Prevalence: 3.8-4.6% • Annual incidence: 4.1 per 1000 in women• 0.6 per 1000 in men• Levothyroxine – 3rd most prescribed

medication after simvastatin and ASA. • Simple dx and treatment.

Diagnosis of Primary Hypothyroidism

The Colorado Thyroid survey :-Sensitivity of individual symptoms: 2.9-24.5 % -Likelihood increases with increased # of symptoms.-Absence of symptoms does not exclude dx. -These symptoms are nonspecific.-Common in euthyroid population (20%)-Thus, dx must be made biochemically.

Canaris et al. Arc Intern Med 2000;160:526-534

Effects of grapefruit juice on the absorption of levothyroxine Lilja, JL et al

Br J Clin Pharmacol. 2005 September; 60: 337–341.

Effect of grapefruit juice (200 ml) (•) or water (○) taken three times a day for 3 days on the mean (± SEM) unadjusted serum concentrations of thyroxine in 10 healthy subjects after a single oral dose of 600 µg levothyroxine. On day 3, grapefruit juice (200 ml) or water was

ingested 1 h before, at the same time as, and 1 h after levothyroxine administration

PK Properties of Thyroid Hormones in Certain Clinical Disorders (Contd)

• Food–Soybean, papaya, grapefruit

and coffee can interfere the absorption

PPI and Levothyroxine Absorption

Comparison of %T4 dissolved from various products at pH ranging from 1.2

to 8 at the end of 30 min.

Nutritional Habits affecting L-T4 absorption

•Coffee, especially espresso•Dietary fiber• Soy diet•Grape Fruit juice

Timing of levothyroxine Administration

Timing of Thyroxine Admininstration

• Thyroxine given 30 to 45 mins before breakfast is the best way to treat hypothyroidism

• If thyroxine is taken at other times food interaction, timing of prior meals et have to be controlled.

• Liquid thyroxine preparation (Tyrosint ) may be an alternative way to give thyroxine although this preparation is more expensive

Summary of T4/T3 Combination Therapy Studies

Why treat patients with a combination treatment of T4 + T3 (cont’d)

• In rats that were made hypothyroid by thyroidectomy or I131 therapy*, T4 monotherapy did not normalize tissue concentrations of T4 and T3.

• About 25-32% of hypothyroid patients on T4 therapy require serum T4 levels at the upper limit of normal range or even higher to normalize T3 levels**.

*Escobar-Morrele HF, et al 1996 Endocrinology 137:2490. **Utiger RD, et al 1994 N Engl J Med 331:1302.

Combination Treatment in Patients with Deiodinase Polymorphisms

• Polymorphisms in D2 may explain why normal serum levels of T3 may not be sufficient to normalize symptoms of hypothyroidism in certain patients receiving T4 alone

• The presence of D2-Thr92 Ala polymorphism is associated with a preference for T4+T3 therapy

Panicker V et al 2009 J Clin Endocinol Metab 96:1623.Appelhof BC et al 2005 J Clin Endocrinol Metab 90:2666.

• Patients with rare CC genotype of rs-225014 polymorphism in the deiodinase 2 gene showed a greater improvement on T4+T3 therapy vs. T4 alone.

• Serum T3 levels may not directly reflected intracellular T3 levels because this polymorphism has no impact on circulating T4 or T3 levels

Panicker V et al 2009 J Clin Endorcinol Metab 96:1623.

Combination Treatment in Patients with Deiodinase Polymorphisms (cont’d)

Patients benefiting from T4+T3 therapy

• The following groups of patients may benefit from T4+T3 therapy:–Hypothyroidism resulting from

autoimmune thyroiditis, s/p thyroidectomy or s/p I131 therapy–Patients with certain D2 polymorphisms–Hypothyroid patients who have

depression

Future of T4+T3 therapy?

• Three daily doses of T3 or a long acting slow-releasing form of T3

• Determination of genetic polymorphism (D2 gene) prior to therapy• Personalized therapy!

Monitoring thyroid function

• May take up to 4 months to normalize due to thyrotroph hyperplasia.

• Measure serum TSH 6-8 weeks after initiation or dose change

• Goal TSH < 2.5 mIU/L typically

• Annual monitoring if stable

Chakera et al. Thyroid Res 2011;505239.

Armour® Thyroid 38 mcg levothyroxine9 mcg liothyronine T3 per grain of thyroidInactive ingredients: calcium stearate, dextrose, microcrystalline cellulose, sodium starch glycolate and opadry white.

Studies comparing desiccated thyroid and L-T4

– Since the 1920s, there were many studies that compared the effects of desiccated thyroid and T4.

–These researchers reported that desiccated thyroid and L-T4 effectively increased patients metabolic rates

• Boothby et al in 1926• Thompson et al in 1929 and 1932• Salter et al in 1932• Robertson and Kirkpatrick in 1952• Sturnick in 1961

Studies comparing desiccated thyroid and L-T4– In 1978, Jackson et al evaluated the effect on thyroid status of

changing from desiccated thyroid to L-thyroxine in 40 patients.

– Of 40 pts --- 13 idiopathic hypothyroidism, 3 post-RAI, 1 post-thyroidectomy and 23 euthyroid MNG treated for gland suppression.

– Dose of 156 ± 6 mg thyroid USP was exchanged for 190 ± 90 mcg L-T4.

– This resulted in a decrease of elevated serum T3 levels to high-normal serum T3 and an increase in serum T4 to high normal levels.

– Six of 40 patients experienced hyperthyroid symptoms while on desiccated thyroid USP, which disappeared completely in three and diminished in the other three patients after the change to T4.

Jackson I and Cobb WE: Why Does Anyone Still Use Desiccated Thyroid USP? The American Journal of Medicine: 64, 1978, 284-288.

Studies comparing desiccated thyroid and L-T4– In 1978, Sawin C.T. et al. compared LT4 and DTE in 15 patients with

primary hypothyroidism (6 patients taking oral T4, 3 taking oral desiccated thyroid, and 6 on both regimens).

– The relative potency of LT4 and DTE was evaluated by using the basal level of serum thyrotropin (TSH) and the TSH response to thyrotropin-releasing hormone (TRH) as the end-points for the biologic action of thyroid hormone.

– It was found that the biological activity of T4 in mcg is equivalent to desiccated thyroid in mg.

– However, both of these studies did not use a third-generation TSH assay, free T4 assay or total T3 levels and hence lacked accuracy.

Sawin CT, et al. A Comparison of Thyroxine and Dessicated Thyroid in Patients with primary hypothyroidism,. Metabolism, Vol 27, No 10, 1978.

• In thyroidectomized rats, tissue euthyroidism could be achieved by infusion of both levothyroxine and triiodothyronine and not by levothyroxine alone.

• These observations led to the hypothesis that a triiodothyronine-levothyroxine combination is necessary to restore tissue euthyroidism in patients with hypothyroidism.

Escobar-Morreale HF et al. J Clin Invest. 1995;2828-2838.

Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind,

Crossover Study

Thanh D. Hoang, Cara H. Olsen, Vinh Q. Mai, Patrick W. Clyde and Mohamed K. M. Shakir

J Clin Endocrinol Metab. 2013 Mar 28

Introduction

• Desiccated thyroid extract (DTE) has been used for treating hypothyroidism for several decades

• Presently, the various endocrine organizations do not endorse DTE for treating hypothyroidism

• Many patients (pts) do not report feeling as well when being switched from DTE to levothyroxine therapy

Introduction (cont’d)

• There is still demand for DTE in clinical practice

• Many pts claim that they do not feel as well when switched from DTE to levothyroxine therapy.

Aim of Study

• Our hypothesis was hypothyroid pts on DTE have a decrease in symptoms, an improvement of cognitive function and an increase in sense of well-being / quality of life (QOL) equivalents compared to LT4

Patients and Methods

• Pts (age 18-65 yrs) enroll in the military health care system who had been diagnosed with primary hypothyroidism and were on a stable dose of LT4 for at least 6 months were studied.

• Exclusion criteria included pregnancy, CHD, COPD, etc.

Figure 1. Flow diagram: enrollment, allocation, and completion of the study.

Results

• 78 pts were enrolled and 70 pts completed the study –53 females (76%)–17 males (24%)

Results (cont’d)Parameter ValueAge (years) 50.7 (23-65)Sex

Male 17 (24%)Female 53 (76%)

Cause of HypothyroidismAutoimmune 35%

Idiopathic 14%Post I131 10%

Post Radiation 3%Other 38%

Results (cont’d)Parameter Value

Dose of L-T4 112.4 + 36.3Clinical Measures

HR 73.4 + 11.3Systolic BP 124.7 + 13.5

Diastolic BP 77.6 + 8.1Weight (lbs) 174.3 + 37.6

Results (cont’d)

• Neuropsychological Measures• TSH• Free T4• Total T4• T3 Resin uptake• Free T4 by dialysis• Total T3• Lipid panel• Sex Hormone Binding Globulin

Neuropsychological Measures Included

• GHQ-12• TSQ-36• BDI Score• AMI Score

• VMI Score• VWMI Score• IMI Score• DMI Score

Physical Measurements at the end of DTE treatment period

DTE LT4 p-valueHeart Rate (BPM)

74 + 12 74+12 0.59

Systolic BP (mmHg)

123 + 14 124 +16 0.34

Diastolic (mm Hg)

78 + 9 78 + 9 0.48

Weight (lbs)

173 + 36 176 + 38 <0.001

Neuropsychological Measurements at the end of DTE treatment period vs. the LT4 treatment

periodNeuropsychological Measures

DTE L-T4 p-value

GHQ 10 + 4.3 11 + 4.9 0.98

TSQ-12 12 + 6.7 13 + 6.7 0.12

BDI Score 4.4 + 4.7 4.8 + 4.9 0.47

AMI Score 128 + 13 126 + 13 0.08

VMI Score 121 + 16 120 + 17 0.58

VWMI Score 117+ 15 116 + 16 0.70

IMI Score 124 + 14 123 + 15 0.23

DMI Score 130+ 14 128 + 16 0.22

Results: Biochemical Laboratory Results at the End of DTE Treatment Period vs. L-T4 Treatment

PeriodBiochemical Measures

Normal Values DTE L-T4 p-value

TSH 0.27-4.20 µ IU / mL

1.67 + 0.77 1.30 + 0.63 0.032

Free T4 0.89 – 1.76 ng/dL

0.85 + 0.16 1.36 + 0.27 <0.0001

Total T4 4.5 – 12 µg/dL 5.88 + 1.34 9.26 + 2.05 <0.0001

T3 Resin Uptake

22 – 35% 30.3 + 3.3 31.8 + 3.4 <0.0001

Total T3 60 – 181 ng/dL 139 + 47 89 + 20 <0.0001

Free T4 Direct 0.8 – 2.7 ng/dL 1.21 + 0.35 2.09 + 0.63 <0.0001

LDL < 130 mg/dL 111 + 30 113 + 30 0.42

HDL > 40 mg/dL 61 + 15 63 + 15 0.028

SHBG 17-124 nmol/L 66 + 48 66 + 47 0.95

OR Estimates of Various Predictors for DTE

Parameters OR 95% CI p-valueTSQ 0.76 0.62 – 0.94 0.01VWMI 0.84 0.72 – 0.99 0.03Serum T3 Resin Uptake

6.84 1.4 – 340 0.02

Serum Free T4 <0.001 <0.001 – 0.033 0.02Serum SHBG 1.18 1.009 – 1,387 0.0388

Results : Preferences

• DTE 48.6 % (n=34)• L-T4 18.6%

(n=13)• No preference 32.9%

(n=23)

Conclusions

DTE Therapy• Does not cause significant improvement in

quality of life• However, DTE caused modest weight loss and

nearly half of the study pts expressed preference for DTE over L-T4

• DTE therapy may be suitable for some pts

Pregnancy• Thyroid hormones essential for neuro development of fetus• Overt/ mild thyroid hormone insufficiency associated with

neuropsychological development• Maternal hypothyroidism associated with miscarriage, premature

birth, gestational HTN, low birth weight. • Therapy: 100-150 µg/d or 2.0-2.4 µg/kg BW/day• Women w/ known hypothyroidism need 30-50% increase of LT4

during pregnancy as early as 4-6 weeks gestation.• Increase by 2 tablets per week as soon as pregnancy confirmed.

• Monitor TFT every 4-6 weeks• Reduce LT4 dose postpartum.

Elderly• A progressive increase in TSH with aging• 97.5 centile is about 3.6 mIU/L in pts who are 20–39 yr of age and 5.9

and 7.5 mIU/liter in those who are 70–79 and 80 yr old and older.• LT4 requirement gradually decreases with age• Due to age-related decreases in T4 degradation and in lean body

mass.• Initial dose: LT4 25-50 µg/day in people over 65 yrs old.• Over-replacement: reduced BMD, increased fractures, Afib.• higher TSH associated with longevity in older individuals• Upper limit TSH 7.5.

Surks and Hollowell. JCEM 2007,92(12):4575-4582.

Walter Reed National Military Medical Center

The End!

•Time for questions and discussions