G. Hennemann

The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism

Multiple alterations in the serum concentration of the iodothyronines have been recognized in patients with systemic non-thyroidal illnesses (NTI). Most prominent are the low serum 3,5,3’-triiodothyronine (T3) and elevated 3,3’,5’triiodothyronine (reverse T3, rT3) concentrations, leading to the generally used name ‘low T3 syndrome’ to describe these changes in the serum thyroid hormone parameters (Wartofsky & Burman, 1982). However, a more appropriate description would be ‘sick euthyroid syndrome’, while not only serum T3 concentrations, but all thyroid hormone parameters, including TSH, are often affected. Since the carly description of this syndromc in ill patients (Carter et al., 1974; Bermudez et al., 1975), low serum T3 concentrations have also been found in patients with liver disease (Chopra et d., 1974; Nomura et al., 19751, after stress or surgery (Burr et al., 1975), in patients with chronic renal failure (Finucane et al., 19771, in the elderly sick (Burrows et al., 1977), and after the ingestion of a number of drugs (Table 1). Of course, these changes have to be attributed to the illness only in the absence of an underlying disorder of the hypothalamicpituitary-thyroid axis, and their complete reversal must accompany recovery from the causal illness. The alterations may rcflcct changes in production of thyroid hormone by affecting the thyroid itself, the hypothalamic-pituitarythyroid axis, the peripheral tissue metabolism of the hormoncs, or by a combination of these effects. In practice, the clinician must differentiate the changes in the serum thyroid hormone lcvels induced by illness from those caused by treatable disorders of thyroid function.

Active transport of triiodothyronine (T3) into isolated rat liver cells

Since the receptors for thyroid hormones are located within the cell [I] , these hormones have to be transported from the extracellular compartment through the plasma membrane into the cell. Only scarce and conflicting data concerning this transport mechanism are available. Both diffusion [2-4] and carrier-mediated processes [ 5-71 have been described or suggested. In view of the fact that amino acids [S] are transported through the plasma membrane by active or mediated processes, it is not likely that thyroid hormones enter the cell by diffusion only. In an attempt to gain more insight into the mechanism of cellular uptake of T3 the present study was performed. As a model we have chosen non-proliferative cultures of parenchymal cells from adult rat liver. The use of primary cultures offers a distinct advantage over freshly prepared liver cell suspensions. Cells are given time to recover from the damage associated with the isolation, such as temporary changes in the inability to concentrate amino acids [9] and the increased catabolic state during the first 24 h after isolation [lo] . In this report, we describe the basic characteristics of T3 uptake in this system. A preliminary account of this work has been publi~ed [l I].

INHERITED THYROXINE EXCESS: A SERUM ABNORMALITY DUE TO AN INCREASED AFFINITY FOR MODIFIED ALBUMIN

Further analysis of sera from euthyroid subjects with dominantly‐inherited, elevated serum total thyroxine (T4) and free T4 index but with normal free T4 levels was performed as an extension of a previous study (Hennemann et al., 1979a). Scatchard analysis and isoelectric focusing of whole sera and purified serum fractions suggest that this T4 excess is due to increased T4 binding by modified serum albumin.

Thyroxine Plus Low-Dose, Slow-Release Triiodothyronine Replacement in Hypothyroidism: Proof of Principle

Studies in hypothyroid rats show that, when infused with a combination of thyroxine (T4) plus triiodothyronine (T3) to normalize thyrotropin (TSH), euthyroidism in all organs is only ensured when T(4) and T(3) are administered in a ratio as normally secreted by the rat thyroid. As substitution with T(4)-only results in an abnormal serum T(4)/T(3) ratio, it is also possible that in humans, euthyroidism does not exist at the tissue level in many organs, considering that iodothyronine metabolism in the human and the rat share many similar mechanisms. Recent reports in which cognitive function and well-being are compared in patients with primary hypothyroidism substituted with T(4)-only versus substitution with T(4) plus T(3) result in controversial findings in that either positive or no effects were found. In all these studies T(3) was used in the plain form that results in nonphysiologic serum T(3) peaks. In these studies it is suggested that substitution with T(3 )should preferably be performed with a preparation that slowly releases T(3) to avoid these peaks. In the study reported here we show that treatment of hypothyroid subjects with a combination of T(4) plus slow-release T(3) leads to a considerable improvement of serum T(4) and T(3) values, the T(4)/T(3) ratio and serum TSH as compared to treatment with T(4)- only. Serum T(3) administration with slow-release T(3) did not show serum peaks, in contrast to plain T(3).

Somatostatin Receptor Scintigraphy in Non-Medullary Thyroid Cancer

8 patients with papillary cancer (4 with metastases, 4 in remission), 7 follicular cancer patients (6 with metastases), 2 patients with anaplastic thyroid cancer and 4 other non-medullary thyroid cancer patients all received an intravenous bolus injection of 220 MBq [111In-DTPA-D-Phe1]octreotide. Planar anterior and posterior gamma camera images of head-neck, chest and abdomen were obtained 24 and 48 h after injection. All primary cancers showed [111In-DTPA-D-Phe1] octreotide uptake; none occurred in patients in remission. The results were compared with conventional radio-iodine scintigraphy in patients with metastasised, differentiated thyroid cancer.

A new radioimmunoassay of thyrotropin-releasing hormone

Several radioimmunoassays for the measurement of thyrotropin-releasing hormone (pGlu-His-ProNHI, TRH) have been described. Antisera have been produced mainly by immunization of rabbits with TRH-protein conjugates in which coupling was effected via the imidazole of the histidyl moiety of TRH. For this purpose bis-diazotized benzidine has been most widely used [ 11. In another procedure TRH is reacted with p-diazoniumphenylacetic acid and the derivative is coupled to protein with the aid of a carbodiimide [2,3] . An entirely different approach has been the introduction of an amide bond between pGlu-His-Pro-OH and NH2 -groups of a protein carrier resulting in the formation of a TRH-like structure, i.e., pGlu-His-Pro-NH-protein [4]. We here report the attachment of TRH to hemocyanin (HC) using the bifunctional reagent 1 ,S-difluoro2,4-dinitrobenzene (DFDNB) [5]. Administration of the conjugate to rabbits elicited the production of antisera, which were used in the radioimmunoassay of the hypothalamic hormone.

The essential role of albumin in the active transport of thyroid hormones into primary cultured rat hepatocytes

We have shown that both 3,5,3’-triiodo-Lthyronine (Ta) [l] and Lthyroxine (Td) [2] are taken up by primary cultured hepatocytes of adult rats by two saturable processes and by diffusion. One saturable uptake system shows a high affinity with a low capacity while the second one has lower affinity and higher capacity. The high affinity systems of Ta and T4 are energy dependent in contrast with their low affinity systems [ 1,2]. T4 inhibits the high affinity system of Ts competitively [2] and vice versa (E.P.K., R.D., H.F.B., unpubli~ed). We suggested that the high affinity systems represent a transport function while the uptake systems with low affinity may be involved in binding at the cell surface [ 11. Our results were obtained from incubations of hepatocytes in a medium containing 10 g/l bovine serum albumin. Since similar studies [3] with cultured monkey hepatocarcinoma cells do not show saturable uptake of Ta in the absence or with a low concentration of albumin (“2 g/l), we dpcided to study the effect of albumin on the uptake of Ts in our system. The results here reported show that at <5 g/l albumin, saturable uptake is not observed, in contrast with higher concentrations of albumin. By increasing the concentration of albumin from 5-20 g/l the V max values of both affinity systems of Ts increase, whereas the Km values remain unchanged. It is therefore suggested (a) that albumin is necessary for optimal diffusion through the unstirred waterlayer around the cell in a system of cultured rat hepatocvfes in monolayer and (b) that increasing con-

Hypothyroidism after Thyroidectomy for Graves's Disease: A Search for an Explanation

Out of 38 patients who had undergone subtotal thyroidectomy for Gravess disease seven to 20 years previously 15 developed hypothyroidism. In these 15 patients autoantibodies against thyroid cytoplasm were significantly more frequent than in the 23 euthyroid patients, though there was no difference in the prevalence of autoantibodies against thyroglobulin. Histological examination of the thyroid tissue removed at operation showed that significantly more plasma cells and lymphoid follicles with germinal centres were present in patients who subsequently developed hypothyroidism than in those who remained euthyroid. No differences in the amount of lymphocytic infiltration were seen in hypothyroid and euthyroid patients. The results suggest that B lymphocytes play a part in the development of postoperative hypothyroidism in Gravess disease. It is proposed that Gravess disease and Hashimotos disease are different aspects of the same basic autoimmune process.

Thyroid hormone synthesis, plasma membrane transport and metabolism

The most important iodothyronine secreted by the thyroid gland is 3,5,3’,5’-tetraiodothyronine (thyroxine, T4). Thyroxine has little, if any, biological activity, and is converted to the active hormone par excellence, i.e. 3,5,3’-triiodothyronine (T3). In man about 80% of total plasma T3 production is extrathyroidally converted to T3 (see below), while 20% is secreted by the thyroid gland.

Lowering of serum 3,3',5-triiodothyronine thyroxine ratio in patients with myocardial infarction; relationship with extent of tissue injury.

Abstract. Serial measurements of haematocrit (Ht), plasma thyroxine (T4), triiodothyronine (T3) and α‐hydroxybutyrate dehydroxygenase (α‐HBDH) were performed in patients following myocardial infarction (MI). Infarct size was estimated by mathematical analysis of the change in plasma α‐HBDH activity with time. After an initial small increase Ht decreased 12% until day 9 and remained constant thereafter. Serum T4 did not change during the entire study. Serum T3 decreased to 66% at day 9 and then returned to normal within 2 months. These figures are expressed relative to determinations in the first blood sample obtained within 12 h after MI. A significant correlation between the lowest serum T3/T4 ratio and infarct size was observed. These observations suggest that in these patients the peripheral conversion of T4 into T3 is reduced. This was accompanied by an increased production of reverse T3 as evidenced by observations in one patient.