Management of Hypothyroidism, A Brief Review and Recent Advances K.M. Mohamed Shakir, MD MACP MACE, FRCP, FACN, ECNU Professor of Medicine Uniformed Services University of the Health Sciences & Consultant Endocrinologist at Walter Reed National Military Medical Center Bethesda, 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.
Combination Treatment in Patients with Deiodinase Polymorphisms (cont’d) • 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.
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速 Thyroid 38 mcg levothyroxine 9 mcg liothyronine T3 per grain of thyroid Inactive 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 LT4 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.
â&#x20AC;˘ In thyroidectomized rats, tissue euthyroidism could be achieved by infusion of both levothyroxine and triiodothyronine and not by levothyroxine alone. â&#x20AC;˘ 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 â&#x20AC;˘ 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 â&#x20AC;˘ 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. â&#x20AC;˘ 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 (contâ&#x20AC;&#x2122;d) Parameter Age (years) Sex
Value 50.7 (23-65)
Male Female Cause of Hypothyroidism Autoimmune Idiopathic Post I131 Post Radiation Other
17 (24%) 53 (76%) 35% 14% 10% 3% 38%
Results (contâ&#x20AC;&#x2122;d) Parameter
Value
Dose of L-T4 Clinical Measures HR Systolic BP Diastolic BP Weight (lbs)
112.4 + 36.3 73.4 + 11.3 124.7 + 13.5 77.6 + 8.1 174.3 + 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 Heart Rate 74 + 12 (BPM) Systolic BP 123 + 14 (mmHg) Diastolic 78 + 9 (mm Hg) Weight 173 + 36 (lbs)
LT4 74+12
p-value 0.59
124 +16
0.34
78 + 9
0.48
176 + 38
<0.001
Neuropsychological Measurements at the end of DTE treatment period vs. the LT4 treatment period Neuropsychological 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 Period
Biochemical 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 TSQ VWMI Serum T3 Resin Uptake Serum Free T4 Serum SHBG
OR 0.76 0.84 6.84
95% CI 0.62 – 0.94 0.72 – 0.99 1.4 – 340
p-value 0.01 0.03 0.02
<0.001 1.18
<0.001 – 0.033 0.02 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!
â&#x20AC;˘Time for questions and discussions