Case submitted by Dr Karen Kartun.
History: This 54-year-old woman is referred for a thyroid evaluation. She was originally diagnosed as hyperthyroid about 20 years ago when she presented with complaints of irritability, feeling "hyper" and general malaise. That had been present for many years before her presentation to this physician. She was treated with radioactive iodine at that time at another facility. Those records are not available. She was subsequently given L-T4 replacement therapy but has never been able to get her levels balanced out since that time. She has persistently had an elevated TSH level with an elevated free T4 level on varying doses of thyroid hormone. She is currently treated with Levothroid 212 mcg daily. She has been consistent in taking her medication everyday. Currently she has some complaints of heat intolerance. She has irritable bowel syndrome and some complaints of hair loss. Weight loss has been difficult for her and she maintains the weight in the mid 170s. She has had some increased blotchiness of the skin recently. She has no complaints of edema, muscle cramps, nervousness, palpitations, or tremor. She is troubled by depression which is treated with Effexor. Her mother had a goiter which was resected. She does not know of any other family with thyroid dysfunction.
Past Medical/Surgical History: (1) Thyroid disease as above. (2) Depression. (3) Irritable bowel syndrome. (4) Status post hysterectomy. (5) History of hand and foot surgeries. (6) Hypertension. Medications: (1) Levothroid 212 mcg q.d. (2) Premarin 0.9 mg q.d., (3) Effexor 150 mg b.i.d. (4) Atenolol 25 mg q.d. Allergies: None. Family History: Mother died at 62 with history of thyroid and heart disease. Father died at 68 with a CVA in his history. Siblings - she has a brother who committed suicide and a sister who died of a brain tumor. She has 4 children, one who has had cerebral palsy, the others are healthy.
Social History: She does not smoke cigarettes, drinks alcohol occasionally.
Review of Systems: negative except as above.
Examination: Blood Pressure: 118/66. Height: 5 feet 3.5 inches. Weight: 176 pounds. Pulse: 59. Temperature: 96.4Â°. She was alert and oriented x 3 and well appearing. HEENT: Extraocular movements were intact. Pupils are equal and round. There was no lid lag, there was no proptosis. Visual fields were intact to confrontation. Neck: Supple. No lymph nodes are palpated. Thyroid did not show a goiter. Lungs: Clear to auscultation. Cardiac Exam: Normal S1/S2. Abdomen: Soft and nontender. Back: Negative for CVA or spinal tenderness. Extremities: Negative for edema. Neuro Exam: Shows 2+ deep tendon reflexes and a tremor was noted. Laboratory studies were reviewed. In 11/99 her TSH was 18.23(0.35-6) with a free T4 of 1.79(0.68-1.76), 7/9/01 her TSH was 15.13, free T4 2.09, 8/14/01 TSH 10.62 (0.35-6), free T4 1.87(0.68-1.76), total T3 210 (58-184)with an FSH level of 29.9, LH of 24.3, prolactin 65.8 (1.6- 27.1), and am cortisol 16.8, 8/20/01 TSH 4.98, free T4 2.55, T3 211. All of those laboratory studies were done on doses of thyroid hormone replacement greater than 200 mcg daily.
Evaluation: This is a very strange story and group of laboratory results. It would be extremely helpful to see the original thyroid function tests and Nuclear Medicine scan report from the time of her initial diagnosis 20 years ago even though her symptoms date back even further than that. There are several possible explanations for her levels; (a) patients who do not take their Levothroid regularly as prescribed can get an elevated TSH level. Sometimes if they take a large number of tablets right before their laboratory tests are done in hopes of normalizing their levels you can see the high free T4 level with an elevated TSH, (b) patients with thyroid hormone resistance can have similar levels. This is a genetic disease which is inherited as an autosomal dominant trait. Therefore, we would expect other family members to have been similarly affected. We do not have a definite history of other affected family members though Ms. James suspects that her daughter may have similar problems, or (c) patients' with TSH secreting pituitary adenomas could have similar laboratory values. It seems as if it would be unlikely that a patient with a TSH secreting adenoma would not be made even more hyperthyroid than baseline levels by the addition of the very high doses of L-T4 she is already receiving. Although this has been going on for 20 years it seems hard to imagine that a TSH secreting adenoma could be missed for that many years. However, in reviewing the literature, there are reports that note the length of time from the onset of symptoms to the time of diagnosis varies from 1-27 years. Many of these patients have received I-131 therapy in the past. Bonnie does not have a goiter and she does not have visual field defects that are obvious. Her FSH and LH are appropriately elevated for a menopausal woman. Her prolactin is moderately elevated and TSH secreting adenomas can co-secrete prolactin or possibly a pituitary tumor can cause stalk compression leading to an elevated prolactin level. Hypothyroidism can also cause prolactin levels to go up because TRH is a prolactin secretagogue. Her cortisol levels are reasonable. Assuming that the patient is honest and her compliance with her therapy has been good we need to differentiate between the latter 2 possibilities. An SHBG is elevated in patients with adenomas and normal in those with thyroid hormone resistance. An alpha subunit is elevated in adenomas and normal in resistance to thyroid hormone. If this were an adenoma the patient theoretically would not require L-T4 therapy and if we decrease it or stop it she should still have an elevated free T4 level unless her prior radioactive iodine therapy did knock out her endogenous thyroid function and her TSH is not suppressible by the overdosage of L-T4 therapy she is currently receiving. We do need to tease these things out. The plan is as follows: (1) Decrease L-T4 to 150 mcg daily and repeat thyroid function tests in 6 weeks. (2) Will check a TSH, a free T4, a total T3, a prolactin, an IGF-1 level today and an SHBG and an alpha subunit. (3) It is okay to go ahead with the pituitary MRI scheduled for 10/23 but no therapy should be instituted prior to obtaining the results of the above laboratory studies. Additional results since the date of the initial consultation-- 10/12/01 SHBG 49.1 (18-114) , PROLACTIN 50.0 (1.6-27.1) , T3 165 (58-184) ,FREE T4 1.80 (0.68-1.76) ,TSH 10.55 (0.3506) IGF-1 138 (90-360) ,ALPHA SUB UNIT 0.2 10/23/01 MRI-vague hypodensity (<1cm) in the right inferolateral pituitary which persists with contrast enhancement. Stalk and chiasm normal. There was mild sloping of the sellar floor. On 150mcg L-T4 QD: 11/28/01 T3 143 (58-184) ,FREE T4 1.29 (0.68-1.76) ,TSH 43.98 (0.35-6)
(12/15/01): I just got back another interesting piece of information. I had the case patient's daughter tested. Her TSH is 1.92 (0.35-6), her free T4 is 2.08 (0.68-1.76) and her total T3 is 236 (58-184). She is not on any thyroid hormone and has never had any form of thyroid treatment. This looks to me like thyroid hormone resistance in this family. Would you agree? If so how do I determine the appropriate levels of free T4/TSH at which to keep the case patient?
Karen Kartun, M.D.
Department of Medicine
Division of Endocrinology
9985 Sierra Avenue
Fontana, CA 92335
From the follow-up on this case, it is obvious that Dr. Kartun does not need the help of "an expert". Short of demonstrating a mutation in the thyroid hormone receptor (TR) beta gene, the diagnosis of resistance to thyroid hormone (RTH) is almost certain. I would like, however, to take this opportunity to make a few comment that may be helpful to practicing physicians. 1. Because RTH is inherited, a simple and direct approach to the diagnosis is to test family members. This always proves to be cost effective, considering the additional tests, such as MRI, often used to rule out alternative diagnosis, are quite pricey. Testing family members is particularly helpful when the study of the key case is complicated by prior ablative therapy and the requirement of hormone replacement. The fact that RTH is inherited as a dominant trait reduces the number of individuals that need to be examined, since, one of the parents must be affected and 50% of siblings and progeny would manifest the phenotype (high serum free T4 and T3 levels with normal TSH). 2. Having said that study of family members is the cornerstone in the diagnosis, it is important to note that 10% of TR beta gene mutation occur de novo. Thus, the key case may be the first family member carrying the TR beta gene mutation. Furthermore, in another 10% of individuals with RTH, the phenotype is not caused by mutations in the TR beta gene. In such instances, additional tests are required to establish the diagnosis. 3. A solid clinical proof that elevated serum free T4 and free T3 levels with non-suppressed TSH is due to RTH is the measurement of responses to exogenous thyroid hormone given in incremental doses. A relatively simple and established protocol is the administration of graded doses of T3 (50, 100, and 200 micrograms/day) each given in two divided doses for three days. The baseline and following each dose central and peripheral parameters of thyroid hormone action are measured and the changes compared to data available from unaffected controls. Baseline measurements of peripheral markers of thyroid hormone action, such as, cholesterol, SHBG (measured in this case), ferritin, and creatine kinase are of little value because of the broad normal range and unrelated conditions that could affect their levels. It is the change in their response to thyroid hormone administration that is valuable for the diagnosis of RTH. 4. Finally, I would like to point out several findings in Dr. Kartun's case that are of interest or important in the differential diagnosis as well as additional simple tests that could have been of diagnostic value. a. Slight elevation of the serum free T4 concentration without TSH suppression is not uncommon in individuals on L-T4 replacement. However, in such instances, T3 remains in the normal range. Similarly, patients with familial dysalbuminemic hyperthyroxinemia (FDH) present with high T4 and even high free T4 levels (measured by direct methods) and non-suppressed TSH. With only rare exceptions, also these individuals have normal serum T3 levels. Thus, in considering the diagnosis of RTH, both free T4 and free T3 must be measured. b. Since RTH is most commonly mistaken as autoimmune thyroid disease (Graves'), the absence of thyroid peroxidase, thyroglobulin and TSH receptor antibodies could point towards the proper diagnosis. c. When goiter is absent and in patients who have not received prior ablative therapy, measurement of the thyroidal radioiodide uptake could be of help. It should be high in RTH but normal in thyroid hormone transport defects, such as FDH. d. Serum prolactin is occasionally high in individuals with hypothyroidism. This is also the case in individuals with RTH who are inadequately replaced with thyroid hormone following ablative therapy. e. A normal alpha subunit and a normal response of TSH to TRH should be sufficient as preliminary tests for TSH producing adenoma. MRI of the pituitary which can be often abnormal due to incidentalomas, should be reserved for those patients who have no living relatives available for testing or when thyroid function tests in family members have proven to be normal. . Recommendations regarding Dr. Kartun's case: a. The patient should be placed on sufficient amount of thyroid hormone to maintain a normal TSH level. If sinus tachycardia develops, Atenolol should be added to the treatment regiment. b. The remainder of the patient's children should be tested. Those with abnormal thyroid function tests should be informed and given letters explaining the cause. They should be instructed to provide this letter to any physician who proposes treatment for their thyroid tests abnormalities. c. Identification of the genetic defect is not mandatory. However, in families in whom RTH is associated with growth retardation, mental retardation or severe attention deficit disorder, identification of the mutation could aid in providing future prenatal diagnosis.
Dr. Samuel Refetoff