Correlation between Histopathology and Signal Loss on Spin-Echo T2-Weighted MR Images of the Inner Ear: Distinguishing Artifacts from Anatomy.

BACKGROUND AND PURPOSE: MR imaging of the inner ear on heavily T2-weighted sequences frequently has areas of signal loss in the vestibule. The aim of the present study was to correlate the anatomic structures of the vestibule with areas of low signal intensity. MATERIALS AND METHODS: We reviewed T2-weighted spin-echo MR imaging studies of the internal auditory canal from 27 cases and cataloged signal intensity variations in the vestibulum of inner ears. Using a histologic preparation of a fully mounted human ear, we prepared 3D reconstructions showing the regions of sensory epithelia (semicircular canal cristae, utricular, and saccular maculae). Regions of low signal intensity were reconstructed in 3D, categorized by appearance, and compared with the 3D histologic preparation. RESULTS: The region corresponding to the lateral semicircular canal crista showed signal loss in most studies (94%). In the utricle, a focus of signal loss occurred in the anterior-cranial portion of the utricle and corresponded to the location of the utricular macula and associated nerve on histopathologic specimens (63% of studies). Additional areas of low signal were observed in the vestibule, corresponding to the fluid-filled endolymphatic space and not to a solid anatomic structure. CONCLUSIONS: Small foci of signal loss within the inner ear vestibule on T2-weighted spin-echo images correlate with anatomic structures, including the lateral semicircular canal crista and the utricular macula. More posterior intensity variations in the endolymphatic space are likely artifacts, potentially representing fluid flow within the endolymph caused by magneto-hydrodynamic Lorentz forces.

Non-invasive measurements of intralabyrinthine pressure changes by electrocochleography and otoacoustic emissions.

By varying the mechanical load on the stapes footplate, intralabyrinthine pressure (ILP) influences the stiffness of the middle ear and modifies its transfer function. This results in a characteristic phase shift of the otoacoustic emissions (OAEs) around 1kHz [Buki, B., Avan, P., Lemaire, J.J., Dordain, M., Chazal, J., Ribari, O., 1996. Otoacoustic emissions: a new tool for monitoring intracranial pressure changes through stapes displacements. Hear. Res. 94, 125-139]. This finding provides non-invasive means of monitoring changes of ILP and indirectly of intracranial pressure. Yet the vulnerability of OAEs to sensorineural hearing loss excludes many patients from being monitored in this manner. Being dependent on the middle-ear transfer function, the phase of the cochlear microphonic potential (CM) around 1kHz should also respond to ILP changes while being less affected by impaired hearing than OAEs. Here, normal volunteers were subjected to body tilt resulting in stepwise changes in their intracranial pressure and ILP. Their CM around 1kHz was recorded by extratympanic electrocochleography and its dependence on body position was compared to that of distortion-product OAEs. The posture-induced CM changes were also monitored in ears with sensorineural deafness and impaired OAEs to assess the usefulness of CM in the presence of hearing impairment. Last, OAEs and CM were simultaneously monitored in gerbils during intracranial pressure changes brought about via an intracranial catheter. The phase and level shifts induced by body tilt in man and intracranial pressure changes in gerbils showed up both in distortion-product OAEs and CM with similar time courses. In normally-hearing subjects, the mean phase shifts reached 16.3 degrees for CM and 41.6 degrees for OAEs, and CM remained large enough in hearing-impaired subjects for ILP to be monitored. The ratio of about two of OAEs to CM phase shifts matched the prediction of middle-ear models allowing for the fact that CM does not travel back through the middle ear while OAEs do. It follows that CM phase around 1kHz provides non-invasive access to ILP changes even if OAEs cannot be measured due to sensorineural hearing loss.

Middle ear influence on otoacoustic emissions. I: noninvasive investigation of the human transmission apparatus and comparison with model results.

Evoked otoacoustic emissions (EOAEs) are generated within the cochlea in response to external sounds, and they can be acoustically detected in the external auditory meatus after backward propagation through the middle ear. In addition to being used to probe the cochlear mechanisms, they are expected to be sensitive to minute changes in middle ear impedance. Systematic measurements of the changes in the vectorial components of EOAEs were carried out after various manipulations of the human middle ear in order to characterize the influence of stiffness and inertia of the stapes and tympanic-membrane systems. For this purpose, stapedius muscle contractions were elicited by high-level contralateral sound, controlled changes in middle ear pressure (range +/-100 daPa) were produced and the tympanic membrane was loaded with water droplets. A computer model of the middle ear network was implemented using a standard lumped-element electric analog of the middle ear (Zwislocki's model). Forward and backward transmission changes were simulated and model predictions were compared to experimental data. Apart from the case of positive middle ear pressures, a close qualitative correspondence was found between model and real-ear results. Each of the effects was characterized by a unique pattern of phase and magnitude changes as a function of frequency, in relation to the mechanical characteristics of the involved subsystem (i.e. stapes stiffness, tympanic-membrane stiffness or mass) and its resonance properties. Owing to their high sensitivity, EOAEs could be helpful for an accurate individual multifrequency analysis of middle ear impedance by comparisons under rest and test conditions.

Middle-ear influence on otoacoustic emissions. II: contributions of posture and intracranial pressure.

Although it seems likely that body tilt or surgically provoked variations in intracranial pressure (ICP) can result in variations of intralabyrinthine pressure, the channels for pressure transmission remain controversial and the reasons why evoked otoacoustic emissions (EOAEs) exhibit attendant modifications are unclear. The theoretical framework implemented in the companion paper [Avan et al. part I, 2000] provides sensitive and non-invasive means to identify the middle-ear mechanism(s) entailed in EOAE changes. It was thus applied to analyze the influence of posture on EOAE phases and magnitudes as a function of frequency, in a series of experiments involving body tilt from sitting to supine (0 degrees or -30 degrees ). Controlled ICP variations were surgically carried out in a series of hydrocephalic patients and the resulting EOAE changes were compared to posture data and model predictions. In all cases, the EOAE changes closely resembled those due to an increase in the stiffness of the stapes' annular ligament, in keeping with the assumption that ICP gets transmitted to intralabyrinthine spaces and modifies the hydrostatic load on the stapes, thereby influencing EOAE features. A small additional contribution of middle-ear pressure to EOAE changes was identified in addition to the main stapes component. Dynamical EOAE measurements showed that sudden ICP changes were transmitted to the inner ear within 8-30 s. The high sensitivity of EOAE phases below 2 kHz to ICP changes, together with the absence of any significant confounding middle-ear effect, favors EOAEs for a reliable non-invasive monitoring of ICP and intralabyrinthine pressures.

Olivocochlear efferent vs. middle-ear contributions to the alteration of otoacoustic emissions by contralateral noise.

The medial olivocochlear efferent bundle is the key element of a bilateral efferent reflex activated by sound in either ear and acting directly on cochlear outer hair cells (OHC) via numerous cholinergic synapses. It probably contributes to regulating the mechanical activity of the cochlea. Otoacoustic emissions, being sounds emitted by the cochlea as a reflection of its activity and suppressed by efferent activation, are increasingly considered to be the privileged tool for a noninvasive assessment of the efferent reflex. However, confounding effects on otoacoustic emissions can occur. A primary influence is middle-ear muscle reflex activation, which shares common features with the effects of cochlear efferent activation. We report a systematic comparison of the responses of human otoacoustic emissions to efferent activation by low-level noise in the contralateral ear to various middle-ear manipulations (reflex contractions of the stapedius muscle induced by high-level contralateral noise; moderate middle-ear pressure changes). The profiles of level and phase changes of otoacoustic emissions as a function of frequency were highly specific to the origin of the effects. The changes induced by middle-ear manipulations matched the predictions computed from a standard lumped-element middle-ear model, with one or two peaks around the resonance frequency(ies) of the involved subsystem, stapes or tympanic membrane. In contrast, the efferent effect was completely different, exhibiting a broadband-level suppression associated with a small phase lead. We propose that a careful vector analysis of otoacoustic emission modifications enables the identification of the contribution of the efferent reflex without ambiguity even when it is mixed with middle-ear effects. Thereby, otoacoustic emissions can be used more reliably as noninvasive probes of efferent olivocochlear function.

Detection of early ototoxic effect in testicular-cancer patients treated with cisplatin by transiently evoked otoacoustic emission: a pilot study.

UNLABELLED: The outlook for patients with testicular germ cell cancer was dramatically improved by the introduction of cisplatin. Well-known side effects of cisplatin (nausea, vomiting, nephrotoxicity, myelosuppression) can be managed with preventive methods. The long life expectancy after this therapy draws attention to long-term side effects. The ototoxic side effects were scarcely studied, although nowadays, they can be a dose-limiting side effect of cisplatin. PATIENTS AND METHODS: As the literature shows, the ototoxic side effects of cisplatin have been studied mostly by conventional methods. The authors used transiently evoked otoacoustic emissions to determine whether the administration of 20 mg/m2 body surface cisplatin daily (in combination with other antitumor drugs) for 5 days alters the amplitude of the transient otoacoustic emission. RESULTS: The results did not show any significant amplitude change after 20 mg/m2 cisplatin daily for 5 days, in contrast with other studies that described a broad frequency reduction of the emission amplitude in 30-86% of cases treated with 100 mg/m2 of cisplatin for 1 day. CONCLUSION: The authors suggest that between similarly effective regimens, those containing lower daily cisplatin doses should be used.

[Non-invasive monitoring of intracranial pressure changes through the ear]. / A koponyaüri nyomásváltozások noninvazív monitorozása a fülön keresztül.

Otoacoustic emissions are low energy vibrations generated by the inner ear during the physiologic process of hearing. The authors measured transiently evoked otoacoustic emissions in normal hearing individuals placed in Trendelenburg position and during diagnostic elevation of intracranial pressure in neurosurgical patients. In Trendelenburg position and at elevated intracranial pressure and reproducible phase shift of otoacoustic emissions could be observed. This phase shift was linear to the pressure increase of intracranial liquids. According to the hypothesis of the authors intracranial pressure increase is transmitted to the inner ear (possibly by the cochlear aqueduct) and thereby the mechanical load on the stapes footplate is elevated. This, in turn, causes a stiffening of the annular ligament which changes the angle of the impedance vector and thereby the phase of the whole vibrating system. By measuring the phase of otoacoustic emissions it is possible to monitor intracranial pressure in various clinical states.

[Urinary calcium excretion. (Normal values for urinary calcium/creatinine ratio in Hungary). Multicenter study]. / A kalciumürítés vizsgálata. (A vizelet kalcium/kreatinin hányadosának magyarországi normálértékei). Multicentrikus tanulmány.

Metabolic bone disorders have attracted increasing attention in Hungary due to their significant impact on public health care. Measuring urinary calcium excretion is the first step in the biochemical assessment of bone metabolism. Fasting urinary calcium corrected by creatinine excretion is widely used all over the world. The aim of the present study was to establish standard methods and normal values for the calcium/creatinine ratio in Hungary. Twenty-four centers specializing in metabolic bone diseases participated in the study. Urine standards were sent out to these centers for calcium and creatine determinations. Based on the collected data, methods were corrected in order to achieve similar results for the standards. In the second phase of the study, the normal values for calcium/creatinine ratio were determined in SI units based on the data from 1846 healthy subjects (age 20-80 yrs) including 944 females and 902 males. The normal value for females was 0.438 +/- 0.391 (means +/- SD), and 0.395 +/- 0.352 for males, respectively (p < 0.03). The ratio increased with age in both sexes. The highest values were observed between 60-64 years in women and 70-74 years in men, respectively. After this peak, the calcium/creatinine ratio decreased. The values before and after 45 years of age were significantly different both in women (0.37 +/- 0.36, vs. 0.52 +/- 0.41, p < 0.001; and men (0.32 +/- 0.23, vs. 0.47 +/- 0.45, p < 0.001). The use of this distinction is recommended in the everyday practice.

Otoacoustic emissions: a new tool for monitoring intracranial pressure changes through stapes displacements.

Changes in hydrostatic intracranial pressure (ICP) are thought to be transmitted to cochlear liquids, thereby altering the mechanical load on the stapes footplate. Hence the stiffness of stapes' annular ligament is expected to reflect ICP changes. Corresponding middle-ear transmission changes have been assessed using click-evoked otoacoustic emissions (EOAE) in two experiments. The first one was performed in 22 normal human subjects submitted to posture changes. In the second one, controlled ICP increases were applied to 18 patients in neurosurgery operating theater. EOAEs were monitored in these subjects throughout the experiments and their phases and amplitudes were analyzed as a function of frequency. ICP affected EOAEs in a systematic manner in both experiments, i.e., the main effect of ICP increase was phase lead of EOAE components below 2 kHz without any significant amplitude or frequency shift. Their variations were much more evident than the modifications in middle-ear impedance assessed by standard impedance or admittance measurements. The second experiment led to a quantitative linear relationship between ICP and EOAE phases. It demonstrated that the sensitivity of EOAE phase monitoring technique proves to be quite high, i.e., 55 daPa increases in ICP are readily detected in all subjects. The results are consistent with the predictions of classical middle-ear models as to the transmission alterations induced by ICP-related changes in the stiffness of the annular ligament of the stapes. Non-invasive monitoring of ICP in patients with hydrocephalus treated with ventriculo-peritoneal shunts might be attempted with this technique, although it is restricted to patients with detectable EOAEs (i.e., about 50% in this series).

Moving time window analysis of transiently evoked otoacoustic emissions.

We have developed a technique for off-line analysis of transient otoacoustic emissions. The correlation of two curves was calculated in a moving time-window of 1 ms time sections. By this method it is possible to recognize high-correlation parts, time sections with low correlation, and thus the duration of the emission can be determined. The mean absolute duration of transiently evoked otoacoustic emissions in 36 normal ears was 15.1 +/- 0.69 ms (mean +/- SE). The duration was significantly shorter (9.34 +/- 0.43) in 75 ears with different grades of sensorineural hearing loss. The breakdown of this group into sub-groups according to the width of the high frequency band with elevated threshold showed a correlation between the severity of the hearing loss and the absolute duration.

Atrial natriuretic peptide (ANP) responsiveness in patients with hypothyroidism.

Hypothyroidism is known to be associated with abnormalities of kidney function; recently, low atrial natriuretic peptide (ANP) plasma levels have been reported. Aim of the study was to asses ANP, sodium and water responsiveness to an acute saline load. Twelve patients with established primary hypothyroidism and 9 control subjects were studied. ANP was determined in plasma by RIA with extraction, prior to and after the infusion of saline, 500 ml/h for 4 hours. On a similar albeit liberal sodium diet hypothyroid patients excreted less sodium and water (74 +/- 33 (SD) mumol/min and 0.69 +/- 0.15 ml/min, respectively) than control subjects (110 +/- 52 mumol/min; P < 0.05 and 1.06 +/- 0.53 ml/min; P < 0.025, respectively). However, the infusion of saline resulted in a 3-fold increase of sodium output and more than 2-fold increase in urine flow. The exaggerated responsiveness in sodium excretion in patients with hypothyroidism was associated with significantly decreased pre-infusion ANP plasma levels (16.1 +/- 11.1 pg/ml vs. 44.4 +/- 14.4 pg/ml; P < 0.001) and also with sluggish response to the volume expansion (+24% vs. +48%). A significant correlation was found between serum T4 levels and plasma ANP concentrations in 8 patients (r = 0.689; P < 0.05). Although hypothyroid patients tend to retain sodium on a liberal salt diet, their kidney is capable of vigorously eliminating excess sodium when challenged with an acute saline load. This exaggerated responsiveness of sodium excretion can be demonstrated in spite of a sluggish response in ANP. Subnormal ANP levels in hypothyroidism are probably the result of thyroid deficiency.

Transitory evoked otoacoustic emission (TEOAE) in a child with profound hearing loss.

The case of a 3-month-old, prematurely born boy with auditory brainstem response (ABR), verified profound hearing loss and normal transitory evoked otoacoustic emission is presented. Isolated retrocochlear deafness which did not influence TEOAE is hypothesised as a possible cause. The critical evaluation of results when using TEOAE as a screening method is suggested.

Auditory brainstem potentials in uraemia.

Evoked response audiometry was carried out to assess the viability of the auditory pathway in haemodialysed patients. The latency of the waves III and V and I-V interpeak latencies were significantly longer in the renal patients compared to the control group. The I-V interpeak latency was longer in 8 of our 13 patients than the upper limit (4.38 ms) in our laboratory. The possible cause for the central auditory dysfunction may be multifactorial, including the effect of metastatic calcifications, repeated occurrence of disequilibrium syndrome, or some small, molecular, toxic, metabolic substance. The significance of the different factors may vary among different haemodialysis centres.

[Otoacoustic emission audiometry in neonates and adults]. / Otoakusztikus emissziós hallásvizsgálat újszülött- és felnöttkorban.

The authors discuss the clinical use of the otoacoustic emission audiometry. During the physiological process of sound amplification in the cochlea vibration energy escapes from the inner ear. By the analysis of this sound it is possible to gain information about the function of the cochlea. According to the experiences of the authors the method is extremely useful for screening audiometry in pathological and normal neonates. In adults it can be used for monitoring the cochlear function during ototoxic therapy or noise exposure.

[Determination of hepatitis C antibodies, using the Abbott and the Ortho anti-HCV EIA kits, in chronic liver diseases and patients under hemodialysis for chronic renal failure]. / Hepatitis C vírus ellenanyag meghatározása Abbott és Ortho anti-HCV EIA kittel krónikus májbetegségekben és haemodializált krónikus veseelégtelenségben szenvedökben.

The diagnostic usefulness of anti HCV EIA test of Abbott and Ortho companies were compared. The anti HCV levels determined in the sera of 173 patients with chronic liver diseases and of 17 haemodialysed kidney patients. 109 of 190 (57%) sera were found to be negative and 81 (43%) positive determined by Abbott kit, while 127 (67%) were negative and 63 (30%) were positive by the Ortho kit. Positive results in patients with chronic liver disease were found in 66 patients by Abbott and 58 patients with Ortho Kit. Distribution of positive cases according to the diagnosis is as follows: 29 (57%) out of 51 chronic hepatitis, 17 (61%) out of 28 cirrhosis. Conflicting results were obtained in 20 cases of 190 (11%) when 17 sera were positive by Abbott and negative by ORTHO, and 3 sera were negative by Abbott, and positive by Ortho. The samples close to the cut off and with low positivity with conflicting results were checked again by the neutralization HCV EIA Abbott assay. We found the Abbott HCV EIA test more sensitive in our excellent for screening of large numbers of samples, we recommend to confirm the positive results by a neutralization type test.

Biologic markers in blood reflecting thyroid hormone effect at peripheral tissue level in patients receiving levothyroxine replacement for hypothyroidism.

Plasma fibronectin, serum procollagen-III-peptide and sex-hormone binding globulin as not specific markers of thyroid hormone effect at peripheral tissue level were determined and their values were related with serum levels of TSH, free-thyroxine and triiodothyronine during levothyroxine sodium replacement therapy for hypothyroidism. Low levels of biologic markers characteristic of hypothyroidism were normalized in consequence of hormone replacement and a negative correlation between their serum levels and TSH concentration was demonstrated in most subjects. However, in some patients a discrepancy in the response to levothyroxine between the pituitary and other target organs could be revealed. Additional evidence was disclosed that the pituitary thyrotroph sensitizes a minor decrease in serum thyroxine level, which would not be recognized by other target organs. Furthermore, it was revealed that during L-T4 replacement therapy in a large fraction of patients with subnormal serum TSH concentration blood levels of the measured markers often exceeded the upper limit of the normal range indicating the possibility of "tissue"-thyrotoxicosis beside the pituitary in other target organs, too. According to the present study which takes into consideration markers reflecting end-organ responsiveness to thyroid hormones it is recommended to adjust the dose of levothyroxine to maintain serum TSH in the normal range. For patients with subnormal TSH concentration a close follow-up is obligatory and in case od concomitantly raised free-thyroxine level the reduction of the levothyroxine dosage is proposed.

Impact of a single insulin treatment (imprinting) applied during liver regeneration on hepatic insulin receptor development, blood glucose level and liver function parameters in adult rats.

Rats subjected to partial hepatectomy (surgical removal of two thirds of the liver) showed no appreciable change in serum cholesterol, bilirubin, albumin, total protein and A/G values at 2, 5, 12 and 21 days after the intervention. The enzyme activities characteristic of liver damage (GOT, GPT, LDH, AP) were high in the control group and low in the insulin-imprinted group at 2 days, tended to normalize in both groups at 5 days and changed slightly at 12 days. The blood glucose level was markedly decreased in the control group and to a lesser degree also in the experimental group at 2 and 5 days of sampling. Insulin treatment (loading) performed at 2 and 5 days accounted for a drop of blood glucose which was followed by normalization within 2 h. Starving value and response to insulin loading uniformly fell into the physiological range at 21 days, whereas at 12 days no normalization occurred in either group within 2 h of insulin loading, although the starving value was physiological. The binding capacity of the insulin receptor was markedly low in the control group as long as 12 days, and tended to normalize by 21 days. In the insulin-imprinted group the binding capacity increased over the control at 2 and 5 days and normalized by 12 days.

[Biological markers reflecting peripheral effects of thyroid hormones in autonomous thyroid adenoma]. / Pajzsmirigyhormonok perifériás hatásaira utaló biológiai markerek vizsgálata pajzsmirigy autonom adenomában.

In some patients with functioning thyroid autonomous nodules preclinical hyperthyroidism is detected. It is important to know, whether in this intermediate clinical state beside the suppression of pituitary TSH secretion other target organs are also affected by serum free-thyroxine and free-triiodothyronine levels still within the normal range. Determining some sensitive, but not specific biologic markers reflecting the impact of thyroid hormones at the peripheral tissue level, it was demonstrated that in the group of preclinical hyperthyroidism the mean level of plasma fibronectin exceeded that of the controls (mean +/- S. D.: 583.5 +/- 163.9 vs. 424.2 +/- 84.1 micrograms/ml, p less than 0.001), serum procollagen-III-peptide concentration was already significantly raised, though its value was still within the normal range (mean +/- S. D.: 0.73 +/- 0.17 vs. 0.57 +/- 0.16 U/ml, p less than 0.05), conversely, mean sex-hormone binding globulin level was the same as in euthyroid controls (mean +/- S. D. 47.4 +/- 18.2 vs. 48.3 +/- 16.3 nmol/l). The value of all three parameters was significantly elevated in patients with toxic nodular goiter. Based on the results of this study "tissue"-thyrotoxicosis is suspected in some patients with preclinical hyperthyroidism, which may have therapeutical implications.

[Decreased serum osteocalcin level in non-alcoholic and alcoholic chronic liver diseases]. / Osteocalcin szérum szint csökkenése nem-alkoholos és alkoholos idült májbetegekben.

Serum level of osteocalcin (OC) is believed to be a specific biochemical parameter of bone formation. Decreased serum OC has been reported in alcohol-intoxicated subjects, in patients with primary biliary cirrhosis and in patients with chronic alcoholic liver disease. The question was, whether lower OC level could be detected in patients with nonalcoholic and non-cholestatic chronic liver disease. The serum OC was measured by RIA developed in our laboratory. Results were compared to age and sex matched controls. Decreased OC level was found in 35 out of 47 (74%) patients with non-alcoholic and non-cholestatic liver disease as chronic persistent hepatitis, chronic active hepatitis, fatty liver and cirrhosis, in 21 out of 26 (80%) patients with alcoholic liver disease and in 8 out of 15 (53%) primary biliary cirrhosis. None of the patients had elevated value. There was no correlation between the decreased OC level and the duration or severity of the liver disease and the laboratory parameters as bilirubin, AST, ALT, alkaline phosphatase, albumin, prothrombin, and serum 25-OH-D3 vitamin level. Decreased OC was found also in the patients without cirrhosis. The possible causes are discussed. Relying upon these findings it is supposed that chronic liver disease by itself can influence the osteoblast activity also by some unknown mechanism.

Biologic blood markers reflecting thyroid hormone effect at peripheral tissue level in patients receiving levothyroxine replacement for hypothyroidism.

Plasma fibronectin, serum procollagen-III-peptide and sex-hormone-binding globulin as non-specific markers of thyroid hormone effect at peripheral tissue level were determined and their values were related with serum levels of TSH, free-thyroxine and triiodothyronine during levothyroxine sodium replacement therapy for hypothyroidism. Low levels of biologic markers characteristic of hypothyroidism were normalized in consequence of hormone replacement and a negative correlation between their serum levels, and TSH concentration was demonstrated in most subjects. However, in some patients a discrepancy in the response to levothyroxine between the pituitary and other target organs was revealed. Additional evidence was disclosed that the pituitary thyrotroph sensitizes a minor decrease in serum thyroxine level, which would not be recognized by other target organs. Furthermore, it was revealed that during L-T4 replacement therapy in a large fraction of patients with subnormal serum TSH concentration blood levels of the measured markers often exceeded the upper limit of the normal range indicating a possibility of "tissue" thyrotoxicosis, besides the pituitary, in other target organs, too. According to the present study, which takes into consideration markers reflecting end-organ responsiveness to thyroid hormones, it is recommended to adjust the dose of levothyroxine to maintain serum TSH in the normal range. For patients with subnormal TSH concentration a close follow-up is obligatory and in case of concomitantly raised free-thyroxine level the reduction of the levothyroxine dosage is proposed.