Observations on the Nature of the Underlying Disorder and the Occurrence of Associated Plasma Transport Abnormalities in a Patient with an Idiopathic Increase in the Plasma Thyroxine- binding Globulin Sidney H. Ingbar, … , Christine Waterhouse, Paul Cushman J Clin Invest. 1964;43(12):2266-2271. https://doi.org/10.1172/JCI105100. Research Article Find the latest version: https://jci.me/105100/pdf Journal of Clinical Investigation Vol. 43, No. 12, 1964 Observations on the Nature of the Underlying Disorder and the Occurrence of Associated Plasma Transport Ab- normalities in a Patient with an Idiopathic Increase in the Plasma Thyroxine- binding Globulin* SIDNEY H. INGBAR, CHRISTINE WATERHOUSE, AND PAUL CUSHMAN t (From the Thorndike Memorial Laboratory, Second and Fourth [Harvard] Medical Services, Boston, City Hospital, and the Department of Medicine, Harvard Medical School, Boston, Mass., and the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, N. Y.) Since its discovery in 1952, much has been sponse to pregnancy or to the administration of learned concerning the thyroxine (T4)-binding estrogenic hormones, studies of these three pro- globulin of human plasma (TBG) [cf. Reviews teins, as well as the iron-binding globulin (trans- (1, 2)]. Although its concentration in plasma ferrin), in the serum of this patient were conducted has not been directly measured and is presum- in the basal state and during administration ably very low, the capacity of TBG to bind T4 is of large doses of diethylstilbestrol. The re- readily measured and is normally about 20 ug sponses of TBG and transferrin to an anabolic per 100 ml of serum or plasma (1). Recently, steroid, norethandrolone, were also assessed. several patients have been described in whom the T4-binding capacity of TBG is either greatly in- Methods creased or decreased, apparently on a hereditary Case history. Patient F. H. (Strong Memorial Hos- basis (3-8). Physiological studies in such pa- pital no. 46-32-67), a 66-year-old white female, was first tients have contributed much to a formulation of seen in 1958 and complained at that time of episodes of the role of this protein in the peripheral metabo- giddiness and vertigo, anxiety, tachycardia, and diaphore- lism of T4 (3, 5, 7, 8). On the other hand, little sis of about six months' duration. Weight loss, heat of intolerance, tremor, and palpitations were denied. A has been done to elucidate either the cause the goiter had been noted 40 years earlier and had not protein abnormality itself or the presence of asso- changed in the interim. The patient denied having re- ciated abnormalities in other plasma transport ceived any iodine-containing or hormonal medication. proteins. Physical examination revealed the blood pressure to be The availability of a patient with an apparently 100/85, the pulse rate 88. The thyroid gland was dif- in fusely enlarged, apparently without thrill, bruit, or nod- idiopathic increase the T4-binding capacity of ules. There were no physical signs of hypermetabolism. TBG has made possible further studies of this Significant laboratory data included the following: disorder. Since ceruloplasmin [cf. Review (9)] BMR, + 12%,, + 3%o; thyroidal 24-hour I's' uptake, 20%, and the corticosteroid-binding globulin (trans- 22%; serum protein-bound iodine (PBI), 11.2, 11.6, 10.6, cortin) (10-14), like TBG (15-17), normally in- 9.2 ,ug per 100 ml. trial of methimazole crease in concentration or in re- In view of the increased PBI, a binding activity was initiated. At a dosage of 30 mg daily, symptoms ap- * Submitted for publication June 29, 1964; accepted parently cleared, but the PBI remained 9.0 and 9.2 /Ag per July 27, 1964. 100 ml after 8 months of treatment. When the dose of Supported in part by research grant no. AM-00267-10 methimazole was increased to 40 mg daily, clinical signs from the National Institute of Arthritis and Metabolic of myxedema appeared, and the PBI declined to 0.9 ,ug Diseases, Bethesda, Md., and in part by U. S. Public per 100 ml. Methimazole was discontinued, and several Health Service research grant no. FR 44-03 from the weeks later, in May of 1960, 5 mc of In was adminis- Division of Research Facilities and Resources, National tered. The patient was asymptomatic at this time and Institutes of Health, Bethesda, Md. has remained so subsequently, although her thyroid de- t Present address: St. Luke's Hospital, New York, creased in size. In March 1961, laboratory tests revealed: N. Y. BMR, -7%, -5%O; PBI, 10.7 /Ag per 100 ml; serum 2266 IDIOPATHIC INCREASE IN TBG 2267 butanol extractable iodine, 8.8 ,ug per 100 ml; 24-hour thyroidal I3' uptake, 38%, decreasing to 5% after 7 days of treatment with 3,5,3'-triiodothyronine, 100 ,ug daily. In June 1961, an increase in the binding activity of 'o _ 0 0 0000 TBG was considered as the possible cause of her ab- 4t4 0 O 00 0\ U) normal PBI. Electrophoretic studies of her serum re- vealed the T4-binding activity of TBG to be greatly in- I - in 00 r 04 tn 440 - 0 ,I.o04- ' creased. In view of the persistently normal values for u4 CN o - BMR and thyroidal I131 uptake, both before and after .0 I'31 therapy, and the normal thyroid suppression test, it oE 4) .% would appear likely that the patient's persistently in- 00 N o creased PBI was never due to thyrotoxicosis, but was, 1') instead, a consequence of increased hormonal binding in the plasma. =.4 In August 1962, the patient was admitted to the Strong Memorial Hospital to receive a 3-week course of diethylstilbestrol, 30 mg daily. The control cervical '0o 00 0 smear revealed no evidence of estrogenic effect. A pro- 0* _44- gressive effect was noted during treatment, however, Cd and was marked by the time diethylstilbestrol was dis- 0 0 u) m o 0u)Cu 00Cr continued. Withdrawal vaginal bleeding followed a 0o'.nn 13 (1 14f\ 0 44 0 few days thereafter. 0 The patient was readmitted in November 1962 to re- 0t 4 U4s cq 0 (7 It'O o oc ceive a 3-week course of norethandrolone, 50 mg daily. During the treatment period, serum glutamic-oxalacetic o44 4.) 0 transaminase values increased from 20 to 60 U. Serum 00 0 t 0000tt-00 000 .0 bilirubin upon completion of therapy was 1 mg per 100 ml. .0 0 Balance studies performed during and after the a .k ot-cl C14 + ,O -9c4 treatment period revealed that norethandrolone induced o Fs in Mc4000 en 00040t0 significant nitrogen retention. 4en enX 00 u CNmM ) 4N- 000X In July of 1963, the patient was readmitted for a 44*4 second course of diethylstilbestrol treatment in order to 0 ~o .0F tne\0 C1400 f'14 '.4.4'3' verify the previously observed findings with regard to ._ a . the effects of this agent on T4-binding and to assess its 00-00 Lnnin c Lnm(4C4n to0 000Lto c ._ 4o ) bO a effects on other plasma transport proteins. o44 .0 Procedure. ._50 Thyroxine-binding capacities of TBG and H H thyroxine-binding prealbumin (TBPA) in serum were 0>4 measured by methods described in detail earlier, em- 0.x ploying paper electrophoresis in Tris-maleate buffer, pH .00 8.6 (7). Concomitantly, the distribution of tracer quan- 0 .04- t4 ''.3' "200'U- tities of P`31-labeled thyroxine, reflecting the binding of D>4c0 4 the endogenous hormone, was also assessed. Analyses 0 for the proportion of unbound T4 in serum were carried 0 3N _ )CZ 4 -00 00044 out by an equilibrium dialysis technique, recently de- 000 0 scribed in abstract form (18), to be described in detail la0 in a later communication. Serum PBI was measured by '.3 e 204e '2 b b4c 00' b440 IC nSo-oZ0.4 ._ a modification of the method of Zak (19). Plasma .5 17-OH corticosteroids were analyzed by the method of -.4 . - Hu m Peterson, Karrer, and Guerra (20), and transcortin H .c concentrations by the method of Daughaday, Adler, 0_>4 Mariz, and Rasinski (14). Ceruloplasmin was meas- 4)0 0 0 ured by the method of Scheinberg and Morell (21). a11 Serum iron-binding were measured capacities by the .0 method of Peters, Biovanniello, Apt, and Ross (22). 0 Coo o to o 0o > 4 Results 50x x aO a 11 Results obtained are presented in Table I and Figure 1. In the basal state, the patient's PBI on 2268 S. H. INGBAR, C. WATERHOUSE, AND P. CUSHMAN *-- P81 (Ag//COOmL) (28.2 per 100 ml) were within normal limits, x-x TBG Binding COacity (,ug r7 //OOmL x /O -') /ug &- --& Free 74 (%ftofo/x /02) as was the concentration of ceruloplasmin (25.4 o-o Free T4 Iodine (gg//OOmL x /03) mg per 100 ml). Total serum iron-binding ca- DIETHYLSTILBESTROL NORETHANDROLONE was at the upper (30 mg/day) (50mg/day) pacity limit of the normal range 12 (356 and 404 ptg per 100 ml), although serum iron 'o0 was normal (152 and 142 ug per 100 ml). 0~ 0 Response to diethylstilbestrol. During two 8 separate 3-week trials of diethylstilbestrol, no sig- 61- x A nificant change in the PBI, in the proportion of 4 unbound T4, or in the concentration of free T4- or- Q iodine in the serum occurred. The T4-binding 2 - capacity of TBG showed little, if any, response I to estrogen administration. During the first trial, 0 1 2 3 0 2 3 WEEKS OF TREATMENT WEEKS OF TREATMENT the binding capacity was 52 ug per 100 ml in the FIG.