R. Docter

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.

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-

THE IMPORTANCE OF PITUITARY TUMOUR SIZE IN PATIENTS WITH HYPERPROLACTINAEMIA IN RELATION TO HORMONAL VARIABLES AND EXTRASELLAR EXTENSION OF TUMOUR

In sixty‐two patients with hyperprolactinaemia and a pituitary tumour (without growth hormone excess) we studied the importance of the size of the sella turcica plus extrasellar tissue (if present) in relation to the prevalence of extrasellar extension and impaired hormonal reserve. A lateral tumour area, V of 3 cm2, turned out to be a critical value both in the development of extrasellar extension of the pituitary adenoma as well as in the development of insufficiency of the pituitary‐gonadal, ‐thyroidal and ‐adrenal axis. Extrasellar extension occurred in 44% of the patients. Below the value of 3 cm2 (n= 36) there was only one patient with radiologically detectable significant suprasellar extension. Above the value of 3 cm2 twenty‐four out of twenty‐six patients had significant extrasellar extensions at radiological and perimetrical examination. Taking the size of the sella only, extrasellar extension occurred in one third of the cases with a sellar size between 2 and 3 cm2. There was a strongly positive correlation between (log) tumour size and (log) basal prolactin level (P < 0·0005). LH, FSH, TSH and ACTH secretion were evaluated by the consecutive administration of LHRH, TRH and metyrapone. Negative correlations were observed between (log) pituitary tumour size and (log) basal LH, FSH and TSH (respectively P < 0·005, P < 0·005, P < 0·025) and between (log) tumour size and (log) Δ LH, Δ FSH, Δ TSH and the plasma Compound S concentration after metyrapone (respectively P < 0·0005, P < 0·005, P < 0·01, P < 0·025). Again the value of the index of tumour size (3 cm2) proved to be critical. Above 3 cm2 a highly significant increase in the incidence of insufficient responses to the stimuli mentioned was observed. Pituitary tumour size may be one of the most important indices used in the management of patients with hyperprolactinaemia and a pituitary tumour.

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.

Degradation of thyrotropin releasing hormone and a related compound by rat liver and kidney homogenate.

The inactivation of the hypothalamic hormone by rat liver and kidney homogenates was studied, using specific radioimmunoassays for the measurement of thyrotropin releasing hormone, pGlu-His-Pro-NH2 (TRH), and for an analogous peptide, pGlu-His-Pro-OH(TRH-OH), which has been proposed as a major metabolite of TRH [NAIR et al., 1971]. The inactivation of TRH and the free acid was found to be rapid. Heat lability and saturation kinetics suggest the involvement of enzymatic processes. In liver homogenate, TRH-OH production from TRH was observed. The accumulation of TRH-OH was substantial in experiments employing near-saturation concentrations of TRH. The liver and kidney are ascribed as major sites for breakdown of TRH in vivo.

Uptake of triiodothyronine sulfate and suppression of thyrotropin secretion in cultured anterior pituitary cells

To investigate the uptake of triiodothyronine sulfate (T3S) and its effect on thyrotropin-releasing hormone (TRH)-induced thyrotropin (TSH) secretion, anterior pituitary cells were isolated from euthyroid rats and cultured for 3 days in medium containing 10% fetal calf serum. Incubation was performed at 37 degrees C in medium containing 0.5% bovine serum albumin (BSA). Exposure of the pituitary cells to TRH (0.1 mumol/L) for 2 hours stimulated TSH secretion by 176%. This effect was reduced by approximately 45% after a 2-hour preincubation with T3 (0.001 to 1 mumol/L). A significant inhibitory effect of T3S on TRH-induced TSH release was only observed at a concentration of 1 mumol/L. The uptake of [125I]T3 after 1 hour of incubation was reduced by 40% +/- 4% (P < .001) by simultaneous addition of 10 nmol/L unlabeled T3, whereas 1 mumol/L T3S was required to obtain a reduction of the [125I]T3 uptake by 34% +/- 2% (P < .001). The amount of T3 present in the unlabeled T3S preparation was 0.25% as determined by radioimmunoassay. When pituitary cells were incubated for 1 hour with [125I]T3S or [125I]T3 (both 50,000 cpm/0.25 mL), the uptake of [125I]T3S expressed as a percentage of the dose was 0.04% +/- 0.02% (mean +/- SE, n = 4), whereas that of [125I]T3 amounted to 3.0% +/- 0.4% (n = 4). In contrast, when hepatocytes were incubated for 1 hour with [125I]T3S, the uptake amounted to 5.1% +/- 0.8% (n = 9), whereas that of [125I]T3 was 22.1% +/- 1.7% (n = 9).(ABSTRACT TRUNCATED AT 250 WORDS)

THE FUNCTION OF THE PITUITARY‐THYROIDAL AXIS IN ACROMEGALIC PATIENTS V. PATIENTS WITH HYPERPROLACTINAEMIA AND A PITUITARY TUMOUR

The function of the pituitary‐thyroidal axis was examined in fifty‐three of sixty‐two patients with hyperprolactinaemia and a pituitary tumour and in forty of forty‐four acromegalic patients, in whom one or more indices of the pituitary‐thyroid function were determined before treatment. In the patients with hyperprolactinaemia and a pituitary tumour, sellar + extrasellar tissue (EST) size showed a significant negative correlation with the response of TSH to TRH (ΔTSH) as well as with the circulating T4 and T3 levels. These correlations were not present in the acromegalic patients. In the prolactinoma group a sharp decrease in mean serum T4 and T3 levels was found at sellar + EST sizes exceeding 3 cm2. In twenty‐three patients with a sellar + EST size of 3 cm2 or more, thirteen (57%) showed a T4 level of less than 6 μg/dl against none of twenty‐eight patients with a sellar + EST size of less than 3 cm2. For T3, using a limit of 120 ng/dl, the corresponding numbers were eight out of thirteen (62%) and none of ten patients respectively. A positive correlation was observed between ΔTSH and the T3 levels but not between ΔTSH and T4, while in the acromegalic patients there was no correlation between TSH reserve and T3 or T4. In the patients with hyperprolactinaemia and a pituitary tumour positive correlations between basal TSH and ΔTSH as well as between T4 and T3 levels were observed. These correlations were not found in the acromegalic patients.