Partial Peripheral Resistance to Thyroid Hormone
MICHAEL M. KAPLAN, MD STEPHEN L. SWARTZ, M.D. P. REED LARSEN, M.D.* Roston. Massachusetts
From the Thyroid Diagnostic Center, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. This report was supported in part by NIH Grants RR-00888, AM 18616 and Research Career Development Award 1 K04 Am 00727-01 (MMK). Requests for reprints should be addressed to Dr. Michael M. Kaplan, Thyroid Diagnostic Center, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. Manuscript accepted May 15.1980. * Investigator, Howard Hughes Medical Institute.
A 33 year old partially thyroidectomized woman was euthyroid when ingesting 500 pg of Gtriiodothyronine (TB)daily. Her condition was evaluated during therapy with daily Ts doses between 50 and 500 pg. She was hypothyroid and had a markedly subnormal oxygen consumption rate when taking 50 to 100 Icg Ts daily, and oxygen consumption did not increase greatly above predicted normal values despite serum Ts concentrations up to 3,200 ng/dl. Her pulse rate, blood pressure, systolic time intervals and exercise tolerance changed minimally and remained within the normal range during the different dosage schedules. Urinary creatine and hydroxyproline, indices of muscle and skeletal protein catabolism, increased normally with higher Ts doses, but serum cholesterol, creatine phospholdnase, calcium and alkaline phosphatase did not change substantially. Basal and thyrotropin-releasing hormone (TRH) stimulated thyrotropin secretion were suppressed during all Ts doses. The prolactin response to TRH was normal at 50 pg TJday and was reduced by higher doses of Ts. Absorption of Ts, serum Ts protein binding and T3 metabolic clearance rates were all within normal limits. The findings in this patient are compared to clinical and biochemical findings in 17 previously described patients. The manifestations of peripheral thyroid hormone resistance are quite variable in the organ systems involved and in the degree of involvement. The molecular basis of the abnormality in our patient remains undefined. A small number of subjects have been described who manifest resistance to thyroid hormones in some of their tissues [l-15]. In general, the resistance is partial and variable in degree from tissue to tissue; moreover, different tissues have been affected in different people or families. We report target tissue responses and the metabolism of exogenous Ts in a woman whose condition falls within the spectrum of partial peripheral resistance to thyroid hormone. Here, the term “peripheral” indicates thyroid hormone target tissues other than the anterior pituitary gland. We then review previously reported cases of this condition. CASE REPORT In 1957, at age 13, the patient received x-ray treatments to the face and neck for acne. In 1967, during her first pregnancy, the right lobe of her thyroid was enlarged. In 1970, during a second pregnancy, she suffered from headaches and fatigue; thyroid function was “low” and she took L-thyroxine (T4). After delivery, without medication, her serum T4 concentration was 4.5 rg/dl. A thyroid scan showed a hypofunctioning area in the lower right lobe of the thyroid. This part of the thyroid was excised and contained a follicular adenoma, surrounded by thyroid tissue exhibiting lymphocytic infiltration and
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PARTIAL PERIPHERAL RESISTANCE TO THYROID HORMONE-KAPLAN
acinar atrophy. Postoperatively, the patient suffered from irritability, fatigue, dry brittle hair and easy weight gain while taking Th in doses up to 0.6 mg orally daily. She felt better taking 1.2mg of T4 daily. In 1972,when taking 0.6 mg T4 daily, she had a pulse rate of 72/min, cool, soft skin, slightly dry hair, brisk reflexes and no palpable thyroid tissue; her serum T4 iodine concentration was 9.4 pg/dl [normal 2.6 to 7.2 pg/dl), and the serum-free Tq concentration was 4.1 ng/dl (normal 0.7 to 2.5 ng/dl). Thyroid replacement therapy was changed to 100 pg Ts orally daily ([email protected]
). She gradually increased her daily dose of Ts to 500 pg. Each time she increased the dose she felt better temporarily, but when she reduced the dose, she suffercd nightmares, irritability, headaches, hair loss and weight gain. In 1974, after one month without thyroid hormone replacement, her serum Td concentration was 5.6 pg/dl and the thyroidal radioiodine uptake was 56 percent at 24 hours. Chemical hypothyroidism was never documented postoperatively. From 1974 to 1977 she took Ts 500 pg orally daily and felt generally well. Her maternal grandmother had a goiter, and a maternal great aunt took thyroid medication of unknown type. There was no consanguinity in the family. In 1977, at age 33, the patient appeared healthy but slightly obese. She was 171 cm tall, had a thyroidectomy scar with no palpable thyroid tissue, a grade l/6systolic ejection murmur at the left sternal border and normal reflexes. The rest of the physical examination was within normal limits. A complete blood count, liver and kidney function tests, blood glucose, chest roentgenogram and electrocardiogram did not reveal any abnormalities. The serum Ts was >2,000 ng/dl=4 hours after her last dose of Ts. Echocardiographic examination showed minimal prolapse of the posterior mitral leaflet.
METHODS Oxygen consumption was measured with a Metabolic Measurement Cart (Beckman Instruments, Fullerton, CA]. When oxygen consumption measurements by this method are compared to standard tables , values for healthy women fall in the range -15 percent to -5 percent. (Aoki T: personal communication). Cardiac evaluation was performed in the Peter Bent Brigham Hospital Non-Invasive Cardiac Laboratory. Serum TJ. TBand TSH concentrations , and antithyroid antibodies (kits from Ames Division, Miles Laboratories. Elkhart, IN] were measured in the Core Laboratory of the Clinical Center. The free fraction of Ts in serum was measured by equilibrium dialysis . Serum was tested for endogenous anti-T3 and anti-T4 antibodies by omitting anti-T3 or anti-T4 rabbit serum from the T3 and T4 assays, which use charcoal separation. Other blood and urine measurements were performed in the Peter Bent Brigham Hospital Clinical Laboratory and Boston Medical Laboratory, Boston, MA. During the metabolic studies the patient took Ts (Cytomel) in a single daily dose orally before breakfast except during metabolic clearance rate studies. Absorption was determined by serum Ts measurements before and 2,4,6,8 and 24 hours after the administration of the Ts. The integrated Ts response was the area under the curve of serum Ts concentration versus
time, from which the area below the line connecting the 0 and .%&hourvalues was subtracted. The response to 500 pg of TRH administered intravenously was assessed by serum TSH and prolactin measurements at -10, 0,20,40,60 and 120 minutes.
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The Ts metabolic clearance rate was determined after the other studies for a particular T3 dose were completed. The same total daily quantity of TJ was given in 10 equal doses, every 2 to 3 hours, and after three days, three io five blood samples were taken at hourly intervals. The Ts metabolic clearance rate was the daily Ts dose divided by the mean serum Ts concentration in the final blood samples. This calculation assumes that Ts was completely absorbed as in normal subjects .
RESULTS Responses of Peripheral Target Tissues to Different Doses of Ta. The patient was studied after taking six doses of Ts.(Cytomel) from 50 to 500 pg/day. The usual doses of T3 required to maintain euthyroidism in athyreotic subjects are 50 to 75 pg/day. The sequence and duration of therapy with Ts are given in Table I. The patient took Ta as a single morning dose at home between metabolic studies. The study periods are designated by the Ts dose (in &day). Periods 500A and 500B refer, respectively, to the long- and short-term courses of 500 pg TJday. Impressive to us, although not subject to quantitative documentation, were the patient’s symptoms. When she took 150 to 500 pg T,/day she denied nervousness, tremor, sweating, palpitations, muscle weakness, heat intolerance and insomnia. In contrast, after four weeks of taking 50 pug TJday and during the four weeks of taking 100 gg Ts/day she suffered from lethargy, fatigue, dry skin, a bloated feeling, paresthesias of the extremities, muscle cramps and irritability. She felt best when taking 200 to 250 pg/day, reporting lack of energy in study period 150 and mild irritability in study period 500B. Results of peripheral target tissue studies are shown in Table I. There was little variation in weight, although dietary intake was not controlled or measured. Mean oxygen consumption rates were within or slightly above the predicted range at daily TB doses 2200 pg and were markedly below the predicted range in study periods 50 and 100. Pulse rates when the patient was at rest varied with the TS dose between 63 f 7/min in study period 50 and 81 f G/min in study period 500A. Blood pressures and systolic time intervals with the patient at rest were within normal limits. The differences in these measurements in different study periods were no greater than differences anticipated from day to day in a healthy subject. Maximum pulse rates during treadmill exercise in study periods 200 and 500B were 180/min and 2OO/min, and the peak plilse pressure product each time was 34 X lo3 mm Hgmin-l, within the normal range. There was no difference in the degree of mitral prolapse in study periods 500A and 50. Urinary excretion rates of creatine and hydroxyproline were supernormal at T3 doses of 150 pg/day or more, but normal in study periods 50 and 100. The serum creatinine phosphokinase level was near the lower limit of normal except in study period 50, when it was near the upper limit of normal.
Patient’s Responses to the Oral Administration of L-triiodothyronine (Ts)
Ts dose @g/day) Duration of Ts dose prior to studies Weight (kg) Oxygen consumption rate kcal/hour percent predicted (normal - 15 to -5) Resting pulse (beats/min f SD)’ Systolic blood pressure, mm Hg f SD+ Diastolic blood pressure, mm Hg f SD+ Systolic time intervals (set) Pre-ejection phase (normal 0.095 f 0.015) Left ventricular ejection time (normal 0.310 f .030)+ Serum cholestrol, mg/dl (normal 130 to 260) Serum creatine phosphokinase, IMiter (normal 50 to 180) Serum calcium, mg/dl (normal 9.1 to 10.9) Serum alkaline phosphatase, IU/ liter (normal 16 to 95) Urinary hydroxyproline, mg/24 hours (normal 15 to 35) Urinary creatine, mg/dl (normal 0.2 to 0.5)
100 4 wk
200 7 wk
77.6 49.1, 55.3
74.2 58.1, 62.7, 61.4
-4.2 85 f 4 128 f 13
81 f6 129 f 3
75 f 5 119f7
63 f 7 121 f 5
66 f 3 111 f6
75 f 6 117 f 11
-8.5, 0, -2.1 79 f 6 126f4
77 f 5
71 f 5
75 f 5
73 f 5
3.2, 19.7, 19.5 0.05, 0.03
61.9. 72.1, 50.0 36.9, 38.4
NOTE: The treatment periods are listed in continuous chronolooic order. NA = data not available. Pulse values are means of 6 to 12 measurements. + Blood pressure values are means of 4 to 8 measurements, all taken in the resting state at various times in the day. $ Left ventricular ejection time was corrected for heart rate. l
There was little change in serum calcium and cholesterol concentration, and alkaline phosphate activity. Tests of the Pituitary-Thyroid Axis. The basal and TRH-stimulated serum TSH concentrations were <1.5 pU/ml at each Ts dose and thyroidal radioiodine uptake was II percent at 24 hours in study periods 500A and 50. Basal serum prolactin concentrations were normal, and varied little with the Ts dose. Serum prolactin concentrations increased slightly after TRH stimulation in study periods 500, 250 and 200 and increased substantially after TRH in study period 50 (Figure 1). Serum Thyroid Hormone Measurements and T3 Metabolism. The patient had no endogenous antibodies against Ts, T4 or thyroglobulin. The antithyroid-microsomal-antibody titer was 1:400 (normal
% 8 5
igure 1. Basal and peak TRH-stimulated serum prolactin concentrations.
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T3 DOSE (wg)
Figure 2. a, serum Ts concentrations prior to and 4 hours after Ts taken in a single oral dose. b, mean serum Ts concentrations when the daily T3 was taken in 10 divided doses. c, integrated increment of serum Ts concentrations above baseline when Ts was taken in a single daily oral dose. d, metabolic clearance rate of Ts.
ure 2a) always occurred 4 hours after the administration
of the dose, as in Ts-treated hypothyroid subjects [ZO]. The peak serum T3 concentration when the patient took 50 pg T3 was 410 ng/dl. Peak serum TS concentrations in hypothyroid patients taking 50 pg Ta daily were 375 f 31 SD . Thus, in our patient oral TS was absorbed normally. In study period 50, the lowest T3 concentration of the day [Figure 2a) 24 hours after the T3 tablets were ingested, varied between 96 and 110 ng/dl, values within the normal range (65 to 160 ng/dl). The daily nadir of the serum Ts concentrations was within or slightly above the normal serum Ts range in all study periods except study period 500, when it averaged 800 ng/dl (Figure 2a). When the Ts dose was divided, the
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mean serum T3 concentration [Figure 2b] was linearly related to the Ts dose, and the coefficient of variation of hourly serum TZ measurements was 115 percent. Sequential serum Ts measurements in healthy subjects exhibit coefficients of variation of 14 to 22 percent [Zl]. Both the peak serum Ts concentration (Figure 2a] and the integrated T3 response (Figure 2c) were also linearly related to the Ta dose when T3 was taken once daily. The metabolic clearance rate estimates (Figure 2d) were similar in study periods 150 and 500B (43.1 and 41.0 liter/day/70 kg), both values higher than the metabolic clearance rate in study period 50 (31.0 liter/day/70 kg). Metabolic clearance rates, for TB, when measured by tracer techniques, are 15.3 to 32.7 liter/day/70 kg in
No. and SCX
Famlllal lhyrold Msease
lhyroid hormone resistance
R (stippled epiphyses. delayed bone
1F 1F 4M 1F
R R .
R R t.
R (sensorineural deafness, achilles reflex time)
7 (mental retardation, psychiatric disturbance)
R’(iiP) R (HP)
hyperthyroidism. thyroid hormone resistance Thyroid hormone resistance Hyiwthyroidism Thyroid nodule Goiter
TSH Secretbn by the Lymphocyte Pituitary Nuclear Gland TX Binding Reference Decreased
we 5 6 7-11
Reported Cases of Tissue Resistance to Thyroid Disease
R (delayed bone age in one boy) R (delayed bone age) R U-W Normal (HP)
. R ((2 Normal
7 (psychiatric disturbance)
[71 [8. 91 [ 10-121
NOTE: R = absent or subnormal response to thyroid hormone; 7 = abnormality of uncertain relationship to thyroid hormone resistance: HP = urinary hydroxyproline excretion; C = urinary creatlne excretion; . . = specific Information is absent in the case reports or that tests of the particular organ system were not performed: + = present: - = absent.
healthy subjects and 25.5 to 108 liter/day/70 spontaneously hyperthyroid patients [Z&27].
COMMENTS our patient’s most striking abnormal quantitative responses to the administration of TJ were found in the cardiovascular system, oxygen consumption and serum cholesterol. Her responses can be compared with those of healthy people taking doses of thyroid hormone comparable to 500 ~g T3 daily for at least two weeks [28-341. These studies are not reported in a uniform manner, but it may be calculated that such treatment causes an increase in the pulse rate of at least 35 percent (mean f SD in 30 healthy subjects, 49 f 9 percent] and that the resting pulse rate is nearly always greater than 9O/min. Oxygen consumption increases by 25 to 75 percent (mean of 25 subjects, 44 percent). and the serum cholesterol concentration decreases by 50 to 140 mg/ dl. Our patient’s mean resting pulse rate when she took 500 pg T3 daily was 81 to 85/min. In three of 14 determinations at that dose it was under 8O/min. Her average resting pulse in period 500A was only 29 percent greater than that in study period 50. There was clearly no in-
trinsic cardiac abnormality since her pulse rate increased to 2OWmin during exercise. Her oxygen consumption rates were clearly subnormal in study periods 50 and 100, when serum TB concentrations were never below normal. 1’3 doses of 50 to 75 &day suffice to maintain hypothyroid patients metabolically normal despite low serum Td concentrations (351; therefore, low serum T4 concentrations cannot explain our patient’s responses. Her oxygen consumption rates in study periods 500A and 500B were 45 percent above those in study period 50, but did not increase greatly above the expected range. Finally, her serum cholesterol in study period 500A was only 26 mg/dl lower than in study period 50. Some of this patient’s responses to the administration of TB were normal. Excretion of urinary creatine and hydroxyproline increased substantially when she took 150 pg T$day or more, indicating accelerated turnover of muscle and bone protein [2,12]. The kinetics of Ts transport into tissues were within normal limits. There was no increase in serum TSH after exogenous TRH during study period 50, showing normal, or possibly increased, sensitivity of the thyrotrophs to TB . The normal increase of serum prolactin after the adminis-
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tration of TRH observed in study period 50 was blunted by the administration of higher doses of Tel, as in spontaneously hyperthyroid subjects (37). The clinical findings and serum Tq and freeT4 concentrations in the patient when she took 0.6 and 1.2 mg T4 daily (see “Case Report”] suggest that she is equally resistant to exogenous Tq and exogenous T3. Previous studies of people whose peripheral tissues are resistant to thyroid hormone are summarized in Table II. Refetoff and DC Groot 13) cite other possible cases of thyroid hormone resistance [38-401, but information concerning the tissue responses is lacking in some of the casts, high serum levels of thyroid hormone induced symptoms of thyrotoxicosis in others, and the maximum dose was much lower than 500 pg T3 in the rest. A separate group of patients demonstrated inappropriately high TSH secretion, whereby supernormal serum TSH concentrations coexist with high serum ‘I’,. TJ, free T4 and T3 concentrations and metabolic manifestations of hyperthyroidism. The findings in this group of patients have been reviewed recently [41,42] and will not be discussed further here. Some thyroid hormone-resistant patients have presented with abnormal growth and development (Cases 1 to 4 [l6]]. Others have presented at various ages with goiter, being otherwise in good health [Cases 6. i’ and 12). One woman was found to be resistant to exogenous thyroid hormone during treatment for myxcdema (Case 5). Abnormal level’s of thyroid hormone in the blood were found in two index cases (Cases 7 and 17) when they were evaluated for nonspecific symptoms. Family members of thyroid hormone-resistant patients have various thyroid abnormalities, including thyroid hormone resistance, euthryoid goiter and hypothyroidism with antithyroid antibodies. The thyroid hormone-resistant patients often have goiters, which sometimes recur (Cases 6, 8 and 12). Measurements of oxygen consumption consistently show abnormally low calorigenic responses to high concentrations of circulating thyroid hormone of endogenous or exogenous origin. Likewise, all of the subjects for whom data are available exhibited blunted hemodynamic responses. Skeletal resistance to thyroid hormone was present in several cases. Mental retardation was present in Case 4, and psychiatric disturbances were present in Cases 4 and 17, raising the possibility of neural resistance to thyroid hormone. Definite neural resistance is only present, however, in Cases 1, 2 and 3. All subjects except one underwent testing of the pituitary-thyroid axis; only our patient demonstrated complete suppression of TRH-
stimulated TSH secretion by normal or near normal concentrations of serum thyroid hormone. To our knowledge, the dynamics of prolactin secretion have not been previously reported in cases of thyroid hormone resistance. In the familial cases, the probable modes of inheritance are autosomal recessive [Cases 1 through 31, autosomal dominant [Cases 7 through 11). and indeterminant, with a mother and her three sons, but not her daughter, affected (Cases 12 through 15). In one sibship. the involved members had decreased numbers of high-affinity T3 binding sites in nuclei of fibroblast and peripheral blood lymphocytes . In other cases, studies of lymphocyte nuclear T3 binding were equivocally abnormal  and normal . The molecular bases for thyroid hormone resistance are not well defined. In Cases 1 through 3. a generalized T3 nuclear receptor defect may be involved. Neither abnormal transport of thyroid hormone from blood into tissues nor impaired extrathyroidal conversion of Td to T3 has yet been demonstrated as a cause, and these are excluded in the present case. Other possibilities include a quantitative abnormality in the number or affinity of thyroid hormone receptors in some tissues or an abnormality in the relationship between thyroid hormone lcvcls and fi-adrenergic-like effects typically present in hyperthyroidism. No case of complete thyroid hormone resistance has been reported; such a condition may well be incompatible with life. Target organ resistance to thyroid hormone appears in diverse forms, perhaps reflecting defects in the different steps in the pathways necessary for the total expression of thyroid hormone action. As methods improve, further studies of thyroid hormone resistance will likely be important aids in mapping those pathways. ACKNOWLEDGMENT These studies were made possible by the cooperation of the patient and the assistance of Dr. Thomas Aoki, Mr. Michael Archangeli, Dr. David Singer, the nursing staff of the Clinical Center of the Brigham and Women’s Hospital. Rodica Emmanuel, M.S. and her staff of the Clinical Center Core Laboratory, and the staff of the Non-Invasive Cardiac Laboratory of the Brigham and Women’s Hospital, We thank Dr. Robert Dluhy for a helpful critique of the manuscript. ADDENDUM Since this paper was submitted pertinent reports have appeared
for publication, [43,44].
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G. 7. a. 9.
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18. 19 20. 21 22
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