An 82 year old woman was admitted to the hospital after she was brought to the ED with a 1 day history of fever, vomiting, and “not acting herself”. Her previous history was pertinent for diabetes, hypertension, chronic renal insufficiency, and schizophrenia. Her only medication was thioridazine. She was found to have an E.coli urinary tract infection and treated with levofloxacin. Because of her abnormal liver function tests, an abdominal sonogram was obtained and acute on chronic cholecystitis with choledocholithiasis was diagnosed. Endoscopic retrograde cholangiopancreatography and sphincterectomy was performed on day 5 of admission. Laparoscopic cholecystectomy was subsequently performed on day 15 of admission. The rest of hospital stay was uneventful and her family reported her mental status to be back to baseline. She remained afebrile. While awaiting nursing home placement, thyroid stimulating hormone (TSH) was checked as a part of a dementia work up and found to be elevated. Additional thyroid function test (TFT) was sent which were as follows:
|27TH DAY OF ADMISSION||34TH DAY OF ADMISSION|
|TSH (Ref 0.34-5.6 µlU/ml)||6.55 µIU/ml (H)||7.73 µIU/ml (H)|
|Total T 4 (Ref 6-12 µg/dl)||28.8 µg/dl (H)||29.8 µg/dl (H)|
|T3 resin uptake (Ref 32-48%)||139.9 % (H)||131.9% (H)|
|Total T3 (Ref 87-178 ng/dl)||43 ng/dl (L)|
In spite of the markedly elevated total T4 and markedly elevated T3 resin uptake, the patient was clinically euthyroid without goiter. Even though her family indicated that she does not usually fully engage in conversation, she replied to greetings and obeyed simple commands appropriately. The family had not detected a change in appetite or weight. On examination, there was no tachycardia, and no neck tenderness or thyroid swelling. No hand tremor was appreciated. Deep tendon reflexes were normal. The family was not aware of previous TFTs and there is no known family history of thyroid disorder. The TFTs repeated 7 days later (Table 1) showed a similar pattern: markedly elevated total T4, markedly elevated T3 resin uptake and a slightly elevated TSH.
This patient exhibited a markedly elevated total T4 and markedly elevated T3 resin uptake. Such a pattern is most commonly associated with hyperthyroidism, and the hyperthyroid state is usually confirmed by finding a suppressed TSH. This patient, however, was not clinically hyperthyroid and not only was the TSH not suppressed, it was actually slightly above the limits of normal.
Because of the negative normal feedback loop of T4 and T3 over TSH, patients who are hyperthyroid due to Graves’ disease, a toxic nodule, thyroiditis or toxic multinodular goiter will have a low TSH level. However, the major disorders to be considered as a differential diagnosis in a patient such as ours with increased total T4 and with inappropriately normal or high TSH are
- TSH-secreting pituitary adenomas
- Abnormalities of T4 Transport in serum
- Resistance to Thyroid hormone (RTH)
TSH-secreting adenoma is characterized by high serum total and free thyroxine (T4) and triiodothyronine (T3) as a result of autonomous pituitary TSH secretion. Clinically most patients have hyperthyroid symptoms and signs with or without goiter. TSH-secreting adenoma is a rare and only account for less than 1 percent of all functioning pituitary tumors and even more less of all cases of hyperthyroidism. 2 3 If clinically suspected, TSH-secreting adenoma can be diagnosed by MRI and an elevated free alpha-subunit of TSH. 4
Abnormalities of T4 Transport in Serum
As approximately 99.97 percent of circulating T4 and 99.7 percent of circulating T3 are bound to binding proteins like thyroxine binding globulin (TBG), transthyretin (TTR) and albumin; factors that affect these binding protein concentration can affect serum total T4 and T3 concentrations even though serum free T4 and T3 concentration are normal 6 and patients are euthyroid clinically.
Elevations in serum thyroxine-binding globulin (TBG excess) and familial dysalbuminemic hyperthyroxinemia are considered as a main differential in a patient like ours with an elevated total T4 with unexpected normal TSH under abnormalities of T4 transport in serum.
TBG excess is detected by doing T3-resin uptake (T3RU) test which was designed to indirectly measure the number of unoccupied T4-binding sites in serum by incubating the patient’s serum with radiolabeled T3 and then adding a resin to bind any remaining radiolabeled T3 not bound to serum proteins (figure 2). TBG excess is characterized by low T3-resin uptake (figure 3) as more radiolabeled T3 binds to TBG in the state of TBG excess and less to the resin. 6 The free-T4 index (FT4I), the product of T3RU and the total T4, is normal in TBG excess.
Familial Dysalbuminemic Hyperthryroxinemia(FHD)
FDH is inherited in an autosomal dominant manner and is characterized by a high serum total T4 concentration and a high calculated serum free T4 index (FT4I) with normal or slightly elevated TSH and normal free T4. This is due to an abnormal mutant serum albumin that has an abnormal binding site with a much greater affinity for thyroxine than that of the hormone-binding sites on thyroxine-binding globulin. 1 In addition, the radiolabeled T3 does not bind to the abnormal albumin but does bind normally to the resin (figure 4). 6
Resistance to Thyroid Hormone (RTH)
RTH is a syndrome characterized by high serum free T4 and free T3 and normal or slightly high serum TSH. RTH is due to the mutations in the thyroid hormone receptor-beta causing reduced responsiveness of target tissue to thyroid hormone. The receptor defect can vary in different organs and RTH generally can be divided into Central (pituitary) resistance and peripheral resistance to thyroid hormone (PRTH). They can be hyperthyroid with goiter as in pituitary resistance or euthyroid or even hypothyroid in peripheral resistance depend on degree of resistance. As RTH is also inherited in an autosomal dominant or recessive manner, similar abnormalities in serum T4 and TSH concentrations can be demonstrated in first-degree relatives. 5 9 10 11
Table 2: Summary of patterns associated with increased T4 and normal or elevated TSH
This patient had a markedly elevated total T4 and markedly elevated T3 resin uptake, initially suggesting hyperthyroidism. Had the TSH not been checked, it would not have been apparent that this patient was, in fact, not hyperthyroid.
Because this patient was clinically euthyroid and had an elevated T3 resin uptake, FDH and peripheral resistance to thyroid hormone (PRTH) became the most likely etiologies (Table 2). To distinguish between these possibilities, free T4, free T3, TBG by RIA were obtained and they all found to be within the reference range (Table 3).
|Free T4 (Ref: 0.8-1.8)||1.7|
|Free T3 (Ref: 230-420)||242|
|Alpha subunit of TSH (Ref: 0.9-3.3 ng/ml for postmenopausal)||0.8|
|TBG by RIA (Ref: 13.5-30.9 µg/ml)||23.2|
Normal free T3, T4 and alpha subunit of TSH make TSH-secreting adenoma and RTH unlikely. We concluded that this patient did not have a TSH secreting pituitary adenoma since she was clinically euthyroid, did not have an elevated alpha subunit level (Table 2,3), and did not have an elevated free T4 (Table 2,3). Elevated T3 resin uptake and normal TBG excluded euthyroid hyperthyroxinemia secondary to TBG excess; but this does suggest FDH and we believe our patient manifested FDH.
There is usually no need to pursue the diagnosis of FDH if the patient is clearly euthyroid and has a normal serum TSH concentration as no treatment intervention is indicated. However, the diagnosis can be established by performing a resin uptake test using radiolabeled T4 rather than radiolabeled T3. 1 As serum from patients with FDH binds more radiolabeled T4 than does serum from normal subjects, increase in serum T4 binding can be demonstated. The diagnosis can also be established by electrophoresis of binding proteins in the presence of radiolabeled T4. Alternatively, serum T4 and free T4 index can be measured in the patient’s relatives; the inheritance of FDH is autosomal dominant. The definitive diagnosis is by gene (DNA) analysis: identifying a mutation in the human serum albumin (HSA) gene. As the patient’s family declined gene analysis, diagnosis by this method was not possible. Fortunately, we believed the patient did not require any form of treatment. The rest of hospital day was uneventful and the patient was discharged to a nursing home.
In conclusion, not all patients with elevated T4 and elevated FT4I are hyperthyroid. Both peripheral resistance to thyroid hormone (PRTH) and FDH are causes of euthyroid hyperthyroxinemia. Our patient most likely manifests FDH which is inherited in an autosomal dominant manner and is characterized by enhanced binding of thyroxine to a mutant form of albumin resulting in elevations in serum thyroxine and the free-thyroxine index (FT4I) with normal TSH and normal free T4. DNA analysis is a rapid and simple method to diagnose FDH. Although the prevalence of the syndrome is still uncertain, it is probably uncommon. When only the total T4 and T3 uptake are measured (or in the past when TSH assays were not as sensitive), patients with FDH were sometimes mistakenly treated for hyperthyroidism. 1
Ruiz M, Rajatanavin R, Young RA, Taylor C, Brown R, Braverman LE, Ingbar SH. Familial dysalbuminemic hyperthyroxinemia: A syndrome that can be confused with thyrotoxicosis. N Engl J Med 1982;306:635-639.
Gesundheit N, Petrick PA, Nissim M, Dahlberg PA, Doppman JL, Emerson CH, Braverman LE, Oldfield EH, Weintraub BD. Thyrotropin-secreting pituitary adenomas: clinical and biochemical heterogeneity. Case reports and follow-up of nine patients. Ann Intern Med 1989; 111:827-35.
Socin HV, Chanson P, Delemer B, Tabarin A, Rohmer V, Mockel J, Stevenaert A, Beckers A. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients. Eur J Endocrinol 2003; 148:433-42.
Douglas S Ross. Euthyroid hyperthyroxinemia and hypothyroxinemia. UpToDate: http://www.utdol.com/utd/content/topic.do?file=thyroid/9588&type=A&selectedTitle
Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, Hauser P, Wiggs E, Weintraub BD. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health prospective study. Ann Intern Med 1995; 123:572-83.
Hayashi Y, Weiss RE, Sarne DH, Yen PM, Sunthornthepvarakul T, Marcocci C, Chin WW, Refetoff S. Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors? J Clin Endocrinol Metab 1995; 80:3246-56.
Refetoff S, Weiss RE. Resistance to thyroid hormone, thyrotropin, and thyrotropin-releasing hormone. UpToDate: http://www.utdol.com/application/topic.asp?file=pediendo/6530&type=A&selectedTitle=1~8