Transcript How do we detect Hypothyroidism?

Hypothyriodism:
Diagnosis, Management and
Optimization of Treatment
Jay Dey MD
Endocrine and Metabolic
Disorders Institute,
Tupelo
Disclosures – None.
Hypothalamic-Pituitary-Thyroid Axis
Hypothalamus TRH
Pituitary
TSH
T4
T3
Target Tissues
Thyroid
Gland
Heart
T4
T3
TR
Liver
Bone
T4  T3
Liver, Muscle
Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.
CNS
How do we detect
Hypothyroidism?
Biochemical Tests for
Thyroid Function
• TSH – Third generation assays
• Free T4 – Closely approximates unbound
thyroxine
• Total T4 – Includes bound and unavailable
thyroxine
• Free T3 – Fluctuates
• T3 uptake, Free T4 index – Indirect
measurements
• Thyroid antibodies – Predictive/Nonspecific
Physical Exam findings in Hypothyroidism
Prevalence of Elevated TSH
(> 5.1 mIU/L) by Age and Gender
% Participants with Elevated TSH
Colorado Thyroid Disease Prevalence Study
(N = 25,862)
Male
24
21
Female
20
16
n=3,020
13.5
12
4
4
4.5 5
18-24
25-34
3
6.5
3.5
5
16
10.5
9
8
15
6
0
35-44
45-54
Age (yr)
Canaris GJ, et al. Arch Int Med. 2000;160:526-534.
55-64
65-74
>74
What causes Hypothyroidism?
• Primary – 95% of
cases
• Secondary – 5% of
cases
– Idiopathic (? Old
Hashimoto’s)
– Hashimoto’s
– Irradiation
– Surgery
– Iodine deficiency
– Medications
– Infiltrative dz
– Pituitary neoplasms
– Hypothalamic
neoplasms
– Congenital
hypopituitarism
– Pituitary necrosis
Hypothyroidism:
Stratification of At-risk Populations*
• Psychiatric Dx
• Women < 35 yrs
• Men < 60 yrs
Lowest Risk
• Women > 35 yrs
• Women > 55 yrs
• Men > 60 yrs
• Diabetes
• Gestation
• Autoimmune disease
• Postpartum
• Hypercholesterolemia
• Family history of
thyroid disease
• Lithium, interferon alpha,
amiodarone
• Recent change in
symptoms
• Thyroid surgery /
radiation
Hypothyroidism
Highest Risk
*Having >1 risk factor incrementally increases the expectation of hypothyroidism.
Canaris G. JOM. 2001;8:27-32,
Canaris G. J Gen Intern Med. 1997;12:544-550.
Special Cases
• Subclinical Hypothyroidism
– Mildly elevated TSH w/normal fT4
– No symptoms (?)
Special Cases
• Subclinical Hypothyroidism
– TSH 5-10mlU/ml – not at risk for
subsequent overt hypothyroidism
– TSH >10mlU/ml – increased risk of
progression to overt hypothyroidism at 120% per year
– Thyroid Ab – presence may also predict
increased risk of progression to overt
hypothyroidism (not yet evidence-based)
Special Cases
• Subclinical Hypothyroidism
– To treat or not to treat?
– Controversial
– No definitive, evidence-based
recommendation
Special Cases
• Subclinical Hypothyroidism
– Individualized approach to treatment
– Consider:
• TSH consistently >10mlU/ml
• High titer of Thyroid Ab
• Risk for osteoporosis, fractures, arrythmias
• Known Hyperhomocysteinemia,
Dyslipidemia, Goiter, Thyroid Nodule,
Pregnancy, (Symptoms)
How do we start therapy?
Levothyroxine LT4 Therapy for
Primary Hypothyroidism
• LT4 is the synthetic version of the naturallyoccurring hormone thyroxine (T4)
• Physicians use TSH to individualize the optimal
LT4 dose
• Small changes in LT4 dose can cause significant
changes in TSH levels
• LT4 is provided in 12 dosage strengths that differ
by as little as 9%
Food and Drug Administration Web site. Active Ingredients. Available at:
http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm. Accessed February 16, 2006.
Starting Therapy
• Otherwise healthy, < 60 yrs, no cardiac Hx:
• ~1.7 g/kg/day
• 6 - 8 weeks F/U TSH, adjust in 25 g dose increments
• Subclinical hypo- may require less LT4
• Older patients, > 60 yrs: require 20 - 30% less
• 50 g/day
• 6 - 8 weeks F/U TSH, 12 - 25 g dose increments
American Thyroid Association Web site. Treatment Guidelines for Patients with Hyperthyroidism and Hypothyroidism. Available at:
http://thyroid.org/professionals/publications/documents/GuidelinesHyperHypo_ 1995.pdf. Accessed February 16, 2006. Hennessey
J. Endocrinologist. 13(6):479-487, Nov/Dec 2003.
Defining Ranges for Serum TSH
• Individual’s range2
• Much narrower than reference range
• 0.5 mU/L over time
• Lab reference range
• Normal TSH values range from 0.4 to 4.1 mU/L
• Defined by values in “normal” population1
• Target treatment range3
• Goals for thyroxine treatment of specific conditions
• Hypothyroidism: 0.5-2.5 mU/L
• Thyroid cancer: undetectable to 0.5 mU/L
1 From
the National Health and Nutrition Examination Survey (NHANES) III. Hollowell JG, et al. J Clin Endocrinol Metab.
2002;87:489-499. 2Andersen, et al. J Clin Endocrinol Metab. 2002;87:1068. 3Adapted from www.Thyroidtoday.com.
Hypothyroidism Treatment Failure: Differential Diagnosis by Elliot G Levy.
How do we monitor ongoing treatment?
• Periodic monitoring essential to ensure
appropriate dosing and consistent effect
• Once TSH normalized:
• Visit frequency decreased to at least Q 6 - 12 months
• TSH should be measured at least annually
• Re-measure TSH (in 8 - 12 weeks) following:
• Change in dosage, type or brand of thyroxine
Singer et al. JAMA. 1995;273:808-812.
Potential Reasons to Increase LT4 Dose
Malabsorption Syndromes
1.
2.
3.
Jejunoileal Bypass Surgery
Short Bowel Syndrome
Cirrhosis
Drugs or Diet
1. Cholestyramine
2. Aluminum Hydroxide
3. Sucralfate
4. Ferrous Sulfate
5. Calcium Carbonate
6. Cation-Exchange Resin
7. High Fiber Diet
8. Infants Fed Soybean Formula
9. ? Excess Soybean in Adults
10.Achlorhydria
11.Proton Pump Inhibitors
12.? H-2 Blockers
ThyroidToday Web site. Hypothyroidism Treatment Failure: Differential Diagnosis. Available at:
http://www.thyroidtoday.com/ExpertOpinions/S320%20Hypothyroidism%20Differential%20Diagnosis.pdf. Accessed February
16, 2006.
Potential Reasons to Increase LT4 Dose
Increased Biliary
Excretion
Decreased Deiodination
of T4 to T3
A. Amiodarone
A.
B.
C.
D.
Phenytoin sodium
Rifampin
Phenobarbital
Carbamazepine
Increased TBG
A. Pregnancy
B. Birth Controls Pills
C. Estrogens
D. Hepatitis
E. Hereditary
Unknown
A. Sertraline
ThyroidToday Web site. Hypothyroidism Treatment Failure: Differential Diagnosis. Available at:
http://www.thyroidtoday.com/ExpertOpinions/S320%20Hypothyroidism%20Differential%20Diagnosis.pdf.
Accessed February 16, 2006.
Small Dose Changes Can
Alter Thyroid Status
• Populations at
greatest risk:
• Elderly patients
with cardiac
disease
• Pregnant women
• Patients with
thyroid cancer
• Consequences of
undertreatment
• Elevated cholesterol levels
• Atherosclerosis and myocardial infarction
• Decreased intellectual function in offspring
of women hypothyroid in early pregnancy
• Consequences of
overtreatment
• Atrial fibrillation
• Bone loss
• Mortality
How Common is Suboptimal T4 Therapy?
30%
Excessive
Thyroxine
Therapy
Inadequate
Thyroxine
Therapy
20%
21%
10%
22%
18%
14%
10%
18%
20%
30%
Ross
1990
32%
18%
27%
Parle
1993
48%
Canaris
2000
40%
Ross DS, et al. JCEM.1990;71:764-769. Parle JV, et al. Br J Gen Pract. 1993;43:107-109.
Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Hollowell J, et al. JCEM. 2002;87:489-499.
15%
Hollowell
2002
33%
Suboptimal Thyroxine Therapy
What Causes It?
•
•
•
•
•
Mild Hypothyroidism
Low Rx dose
Poor compliance
Drug interaction
Dietary interference with
absorption
• Pregnancy
• ↓ Residual gland
function
• Formulation switch
•
•
•
•
Mild Thyrotoxicosis
High Rx dose
Factitious ingestion
Aging with ↓ requirement
for LT4
• Nonsuppressed
endogenous gland
function
• Stopping estrogen
therapy
• Formulation switch
LT4 Dosage Differences
50% 17%
50
-33%
75
-15%
14%
88
100
-12%
Blakesley V, et al. Thyroid. 2004;14:191-200.
12%
12%
112
-11%
10%
125
-10%
10%
137
-9%
150
-9%
17%
175
14%
200
-14% -13%
Pharmacy Substitution of Generics
There is no way to ensure that patients will be given
the same generic from month to month
PHARMetrics Study:
Change in Brand at the Same Dose
•
Retrospective analysis of 196 patients switched to different
LT4 brand at the same dose
•
All patients had been stabilized with TSH 5.0
•
25% had a change in TSH greater than 2.0
% Patients
40%
35%
30%
25%
20%
20%
17%
10%
0%
5%
<0.5
>0.5-1.0
>1.0-1.5
>1.5-2.0
TSH Change (mU/L)
Based on insurance claims data (1997-2002).
>2.0
Absolute TSH
Change
Following
Product Switch
(n=196)
Pharmacy Substitution
Lack of Retitration
• Of the patients whose LT4 was switched at the
pharmacy:

Over 70% were not retested within 90 days of switch

41% were still not retested within 9 months
% Not Retested After a Switch
80%
72%
64%
60%
54%
41%
40%
20%
0%
Within 90 days
PHARMetrics patient database, n = 17,000
Within 120
days
Within 180
days
Within 270
days
Professional Endocrine Associations
Guidance to Physicians and Patients
Physicians should:
• Alert patients that preparation may be switched at
pharmacy
• Encourage patients to ask to remain on the same
preparation at every pharmacy refill
• Make sure patients understand the need to have their
TSH retested and dosing readjusted if their
levothyroxine preparation is switched
The American Thyroid Association Web site. ATA, TES, and AACE express disappointment and concern for the health of
millions of thyroid patients after FDA announces decision to approve generic substitutes for levothyroxine product. Available
at http://www.thyroid.org/professionals/advocacy/04_06_24_fda.html. Accessed February 16, 2006.
Conclusions
•
Write LT4 prescriptions as mcg not mg doses to avoid
errors.
•
Measure serum TSH 6 - 8 weeks after starting or any
dose/product change. If the TSH level is not in the
target range, alter the dose by 10 - 20% increments
•
Check a TSH every 6 - 12 months in stable patients
receiving LT4 replacement
•
Make sure patients understand the important of
adherence and the risks of over and under use of LT4
•
At each visit, assess the patients for signs and
symptoms of over and under treatment
•
Monitor for drug interactions such as LT4 absorption
problems caused by calcium and iron
Practical Advice: Talking to Patients
•
•
•
•
•
•
•
Take LT4 products as prescribed
Take LT4 at the same time everyday
Don’t take LT4 with iron, calcium, antacids
Missed doses can be taken later in the day
Effect of LT4 may take several weeks to notice
If symptoms persist, call the prescribing physician
If other medications change, contact the prescribing
physician
• Look at your pills
– Color, shape, size, inscription
• Expensive co-pays
– Cash prices may be cheaper than co-pays
Alternate options for
thyroid replacement
Thyroid “replacement”
that don’t work
Thyroid “home remedies”
that don’t work