Thyroid Dysfunction in Down Syndrome: Interpretation and Management of Different Patterns of Laboratory Abnormalities

Philip B. May, Jr., M.D.
Developmental Medicine Reviews and Reports
Volume 1, Number 2, October 1998
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Developmental Medicine Reviews and Reports
Department of Medicine
Robert Wood Johnson Medical School
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Autopsy studies and clinical laboratory testing have shown that the thyroid gland is usually abnormal in Down Syndrome. Since dysfunction of the thyroid gland can have serious consequences on the health and well-being of any individual, it is important to accurately assess and treat thyroid gland abnormalities as they are uncovered. In Down Syndrome, there are special problems that should be considered before treatment is initiated. This paper attempts to clarify those considerations and suggests guidelines for optimal treatment of thyroidopathy in Down Syndrome.


Autopsy studies have shown that the thyroid gland is abnormal in virtually all cases of Down Syndrome (1). In addition, clinical laboratory testing has revealed a high frequency of abnormal results when thyroid function has been tested in Down Syndrome, as shown in Table 1. Positive antithyroid antibodies and elevated Thyroid Stimulating Hormone (TSH) are perhaps the most frequently encountered abnormalities, with definite chemical hypothyroidism somewhat less common, and definite chemical hyperthyroidism even more uncommon. While laboratory abnormalities are frequently detected, definite clinical signs and symptoms of thyroid dysfunction may be subtle in Down Syndrome, since Down Syndrome and hypothyroidism share many clinical features. This increases the burden on the laboratory to make the correct diagnosis. When abnormalities are uncovered by testing, it is sometimes unclear what the subsequent management should be. For example, should all cases with isolated TSH elevation be placed on thyroid hormone? How frequently should an individual with isolated positive antithyroid antibody be monitored for thyroid dysfunction? How and when should treatment be initiated and monitored? What is the significance of thyroid dysfunction in Down Syndrome? The following study represents an initial attempt to answer some of these questions by placing observed combinations of abnormalities in various categories for purposes of prospective follow-up. In addition, correlations of thyroid test abnormalities with other abnormalities known to be associated with Down Syndrome were also made.

 Group   Age range   +Antibodies   Elevated TSH   Hyperthyroid   Hypothyroid 
Normal Population (Whickham Survey) >18 years 3% ? 1.1-1.6 % 0.8-1.1%
May (58 cases) 22-61 34% 41% 3% 17%
Kastner (138 cases) 2-59 39% 20% 1.5% 8%
Pueschel (151 cases) 3-21 31% 21% 4.6% 7%
Ugazio (110 cases) 0.3-50 42% ? ? ?
Murdoch (82 cases) 19-65 13% ? 1.2% 16%
Baxter (11 cases) 44-65 45% ? 9% 55%
Hollingsworth (60 cases) 9-65 85% 17% 3.2% 1.6%


The study group consisted of 58 individuals with Down Syndrome who were residents of the Hunterdon Developmental Center, a 650 bed state ICF residential facility located in Clinton, N.J. There were 43 males and 15 females. The mean age was 33 years with a range of 22-61 years. The following tests were performed through our clinical referral laboratory by standard radioimmune techniques: Thyroxine (normal 4.5-12.5 micrograms %), Triiodothyronine (normal 85-185 micrograms %), T3 uptake (23-35%), Thyroid Stimulating Hormone (normal 0.3-5.0 microunits/ml), antimicrosomal antibody (normal less than 1:100), antithyroglobulin antibody (normal less than 1:10), and Hepatitis B surface antigen (normal ratio 0.00-1.70). In addition, 3-view cervical spine x-rays to determine the presence of atlantoaxial instability, fasting morning serum glucose to evaluate for Diabetes Mellitus, and a physical examination to assess for goiter and cardiac murmur were performed in all cases.


The results of the study are demonstrated in Table 2 and Table 3.
In Table 2 nine different possible patterns of thyroid test abnormalities were considered. Groups 1 and 2 were both chemically hypothyroid (i.e. they had a low T4 and elevated TSH). 70% of these chemically hypothyroid individuals had positive antithyroid antibodies (Group 1). All together 20 of 58 cases (18 non-hyperthyroid and 2 hyperthyroid) had elevated antithyroid antibodies and 24 0f 58 cases had elevated TSH. Of those 19 non-hyperthyroid cases with elevated thyroid antibody titers, 15 cases had associated elevation of TSH. The 3 cases with elevated thyroid antibody titers alone (Group 5) had only borderline positive titers and may represent the earliest phase of thyroid disease in Down Syndrome. A distinctly elevated thyroid antibody titer was almost always associated with an elevated TSH, suggesting an autoimmune component for the "diminished thyroid reserve" seen in Down Syndrome. Six cases had borderline elevated TSH with normal T4 and without positive thyroid antibodies at the time of testing (Group 4). It is possible thyroid antibodies could be positive or the TSH could be normal at other testing times (13). The mean TSH in the prehypothyroid autoimmune group (Group 3) was 10.3, while the mean TSH in the prehypothyroid non-autoimmune group (Group 4) was only 6.0.

There were only 3 cases of low T4, elevated TSH, and normal antibody titer (Group 2). Therefore, a low "corrected" T4 (which defines chemical hypothyroidism) is a less common abnormality, but is usually (7 of 10) associated with both an elevated thyroid antibody (AMA and/or ATA) titer and distinctly increased TSH. Only twenty-seven of the 58 cases (47%) had no abnormalities at all (Group 6).

The 2 cases of hyperthyroidism were both associated with antithyroid antibodies (Group 7). There were no cases of hyperthyroidism without antibodies (Group 8). There were 2 cases of borderline low T4 not associated with an elevated TSH (Group 9). These cases could represent the effect of pituitary and/or hypothalamic disease or intercurrent illness on thyroid function.

There was no correlation of thyroid hormone abnormalities with atlantoaxial instability (5 cases), cardiac disease (14 cases) or insulin requiring Diabetes Mellitus (1 case). However, 36 percent of the cases with thyroid abnormalities had a positive Hepatitis B surface antigen, while only 13 percent of those with all normal thyroid tests had a positive Hepatitis B surface antigen, suggesting that abnormalities of thyroid function in Down's Syndrome, may be related to the Hepatitis B carrier state.

However, 36 percent of the cases with thyroid abnormalities had a positive Hepatitis B surface antigen, while only 13 percent of those with all normal thyroid tests had a positive Hepatitis B surface antigen, suggesting that abnormalities of thyroid function in Down's Syndrome, may be related to the Hepatitis B carrier state.

Group Num. Mean Age Anti-Thyroid Antibodies TSH T4 Diagnosis Treatment
1. 7 38 years Elevated High Low Auto-immune Hypothyroidism Thyroid Hormone
2. 3 42 years Normal High Low Hypothyroidism, Antibody negative Thyroid Hormone
3. 8 32 years Elevated High Normal Pre-Hypothyroid, Autoimmune Monitor every 3 months
4. 6 37 years Normal High Normal Pre-Hypothyroid Antibody negative Monitor every 6 Months
5. 3 26 years Elevated Normal Normal Pre-prehypothyroid, autoimmune Monitor every 9 months
6. 27 30 years Normal Normal Normal Pre-prehypothyroid, antibody negative Monitor every 12 months
7. 2 35 years Elevated Low Increased Hyperthyroid, Autoimmune Methimazole, 10 mg b.i.d.
8. 0 - Normal Normal Elevated Hyperthyroid, Antibody negative Methimazole, 10 mg b.i.d.
9. 2 48 years Normal Normal Low Secondary Hypothyroidism "Euthyroid Sick" Additional Evaluation

Group T4 T3 Uptake T3 TSH Anti-Thyroglobulin Antibody Anti-Microsomal Antibody
1. 3.3
2. 3.0
Negative Negative
3. 5.5
4. 6.5
Negative Negative
5. 7.0
6. 7.0
Negative Negative
7. 18.4
0nly one
Negative 1:850
8. - - - - - -
9. 4.5
Negative Negative
Normal Range 4.5-12.5 micrograms% 23-35 % 85-185 micrograms% 0.3-5.0 microunits/ml <1:10 <1:100


The adverse effects of abnormal thyroid function are well-known. An under active thyroid gland leads to cognitive impairment, increased risk of coronary artery heart disease from hypercholesterolemia (14), dry skin, constipation, and anemia. An over active thyroid leads to cardiac arrhythmias, bone demineralization, hyperactivity, and weight loss. These clinical complications of thyroid dysfunction caused by abnormal circulating levels of thyroid hormones (T4 and T3), can be especially harmful to the already impaired individual with Down Syndrome, making it all the more important to make the diagnosis as early as possible. On the other hand, the management of patients with normal circulating levels of thyroid hormone (T4 and T3) but with elevated TSH and/or positive antithyroid antibodies ('prehypothyroid') is less clear. It has been postulated that in individuals with a genetic predisposition to thyroid failure the first markers to appear are thyroid antibodies. As thyroid tissue is destroyed the TSH begins to rise in order to compensate for falling blood levels of thyroid hormone (T4 and T3). With time, the gland is no longer able to compensate, thyroid hormone (T4 and T3) levels fall, and overt clinical signs and symptoms of thyroid gland failure develop (13), (15).

However, it may not be correct that there is an inevitable progressive deterioration of thyroid function in individuals with positive antithyroid antibodies with or without elevated TSH, since antibodies may disappear and TSH levels can fluctuate (13). In addition, one study in non-retarded elderly subjects suggested that only those with markedly elevated TSH (greater than 20) or high titer (greater than 1:1600) antimicrosomal antibody levels (regardless of TSH) should be prophylactically treated. Those with lower elevations of TSH or antibodies did not progress to overt thyroid failure. Thus, it may not be necessary to treat individuals prophylactically with thyroid hormone replacement when only thyroid antibodies and elevated TSH in the absence of low circulating thyroid hormones are present.

This is important because unnecessary treatment with thyroid hormone can lead to bone demineralization and cardiac arrhythmias (17). Since cardiac disease is common in Down Syndrome, using thyroid hormone to treat hypothyroidism even with good indications is not without risks. Similarly, because hematologic abnormalities are common in Down Syndrome antithyroid agents (e.g. PTU, methimizole) must be used with caution.

On the other hand failure to treat either hypothyoidism (common) or hyperthyroidism (rare) can have important consequences with respect to cognition, behavior, and multiple physical problems such as atherosclerosis. Additionally, since hypothyroidism tends to be more frequent in the older age group and since thyroid hormone requirements decrease with age (18), extreme caution should be taken not to over treat. Perhaps use of the new "sensitive" TSH will be helpful in this regard (19-21). Finally, based on these data and review of the literature, we have established the following "therapeutic" guidelines:

  1. Thyroid function in Down Syndrome should be tested annually with T4, T3 uptake, TSH, T3, AMA, ATgA.
  2. If the T4 is low (corrected for binding with T3 uptake) and is associated with an elevated TSH, treat with synthetic thyroid, starting at 25 micrograms per day after baseline Echo-cardiogram and EKG are obtained. If heart disease is present, baseline holter monitoring should be obtained. Increase the thyroid 25 micrograms every 6 weeks or until TSH is normal. Monitor cardiac function carefully.
  3. If the TSH is elevated but the "corrected" T4 is normal, repeat the thyroid tests every 6 months, since the natural history of thyroid dysfunction in Down's Syndrome is not well- studied and there is always a danger of subclinical medication toxicity (17).
  4. If the AMA or ATgA titers are elevated, but the TSH is normal, continue to monitor annually.
  5. If the "corrected" T4 or T3 is elevated (i.e., hyperthyroidism), obtain CBC and begin treatment with Tapazole 10 mg. every 12 hours. Monitor CBC frequently at first.

Further studies (in progress) will determine the validity of these guidelines and ascertain the nature of the relationship between abnormal thyroid function tests and the Hepatitis B carrier state.


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