BACKGROUND: In severe illness, plasma selenium levels are decreased; a decreased activity of the selenoenzyme 5'-deiodinase has been hypothesized to contribute to low tri-iodothyronine (T3) levels in non-thyroidal illness (NTI) syndrome in these patients. OBJECTIVE: To analyse the influence of selenium substitution on thyroid hormone metabolism in patients with severe sepsis. DESIGN: A prospective, randomized, controlled study at the medical internal intensive care unit of the University of Munich. Results are for 41 consecutive patients with severe sepsis with an APACHE II score >15. Patients received either sodium selenite (500 microg/day for the first 3 days, reducing to 250 and then 125 microg/day every 3 days) or a placebo. RESULTS: At study entry, APACHE II score and demographics were identical in both groups. The mean levels of TSH, free tri-iodithyronine and total T3, as well as plasma selenium and selenium-dependent peroxidase (GSH-Px) activity, were decreased. Plasma selenium and GSH-Px activity were normalized on days 3, 7 and 14 in patients receiving selenium (n=21), but remained below normal in the control patients. Patients receiving selenium had a better clinical outcome and thyroid hormone levels normalized earlier. Thyroid hormone levels increased in patients who showed clinical improvement, independent of selenium levels or selenium substitution. CONCLUSIONS: Selenium substitution in patients with NTI improves morbidity, but has no direct effect on the free and total thyroid hormones. In severely ill patients, decreased deiodinase activity due to low plasma selenium levels seems unlikely. After clinical revival, TSH and then the thyroidal hormones normalize independently of selenium substitution.
MW Angstwurm, J Schopohl and R Gaertner
B Gutt, C Hatzack, K Morrison, B Pollinger and J Schopohl
OBJECTIVE: For patients in whom acromegaly persists despite pituitary surgery, conventional pituitary irradiation represents an additional treatment option. A 30-60% cure rate is described in the literature, but these studies did not utilise strict rules of remission, such as "safe" GH levels <2.5 microg/l, and age-adjusted normal IGF-I levels. DESIGN AND METHODS: We report the outcome of 41 patients with acromegaly who received pituitary conventional external irradiation. The median follow-up time was 12.8 years (3.7-43.4 years) post-radiotherapy. RESULTS: The median pre-irradiation GH level was 31.0 microg/l (7.0-210 microg/l). Information on IGF-I levels was only available for 6 patients prior to therapy. Utilising strict rules of remission, one-third (14/41) of our patients had normal biochemical parameters, i.e. "safe" GH (0.5 microg/l (range 0.2-1.6 microg/l)) and normal age-adjusted IGF-I levels (multiple of upper limit of normal range (xULN); 0.45 (0.2-1.0)) at the end of the follow-up period. An additional 9 patients achieved normal levels with adjunctive drug therapy. Furthermore, disease activity was reduced in a considerable proportion of the 18 patients who did not achieve normal biochemical levels (GH: 3.6 microg/l (1.9-15.7 microg/l); xULN of IGF-I: 1.6 (0.9-2.6)). In retrospect, remission is unlikely in patients who had a GH level greater than 52 microg/l (mean+2 s.d. of cured patients) prior to radiotherapy. In addition to the 12 patients with pre-irradiation pituitary functional deficiency, another 11 patients developed symptoms of panhypopituitarism during the 3-year period following irradiation. Within a 6-year period, partial pituitary insufficiency was observed in a further 7 patients, thus necessitating hormone substitution treatment. CONCLUSION: Using strict rules of remission, in our cohort we found both a normalisation of IGF-I and safe GH levels in 34% of patients treated for acromegaly with conventional irradiation therapy.
G. MEHLTRETTER, J. SCHOPOHL, I. LANCRANJAN and K. VON WERDER
M. LOSA, J. ALBA-ROTH, J. MOJTO, J. SCHOPOHL, O.A. MÜLLER and K. VON WERDER
J Roemmler, B Otto, A M Arafat, M Bidlingmaier and J Schopohl
Pegvisomant (peg) is a GH receptor antagonist. In de novo acromegalic patients with high GH levels, ghrelin and leptin levels are reduced, suggesting a direct GH-mediated effect. The aim of our study was to evaluate whether peg treatment in acromegalic patients may abolish the GH impact on ghrelin and leptin levels.
Ghrelin, leptin and endogenous GH were measured in ten peg-treated acromegalic patients (three females/seven males, 47 years (28–57)), ten patients with active (act) and ten patients with inactive disease (inact) as well as in ten gender-, age- and body mass index (BMI)-matched healthy volunteers (controls). Endogenous GH was measured using a special in-house assay without interference by peg; total ghrelin and leptin were determined using a commercial RIA and an immunofluorometric in-house assay respectively.
Age and BMI did not differ significantly between groups. Endogenous GH was significantly higher in peg (6.3 μg/l (1.5–41)) and act (9.3 μg/l (1.7–70)) compared with controls (0.1 μg/l (0.1–3.1)) and inact (0.35 μg/l (0.1–2.0), P<0.001). Ghrelin was significantly higher in peg (232 ng/l (96–351)) compared with act (102 ng/l (33–232), P<0.01), whereas ghrelin was not significantly different between the other groups. Leptin was highest in controls (19 μg/l (4–57)) and lowest in act (6 μg/l (2–21)), but this difference did not reach significance.
Treatment with peg seems to disrupt the feedback loop of ghrelin and GH, leading to elevated ghrelin levels. Furthermore, peg therapy appears not to have a strong impact on leptin levels, as acromegalic patients with and without peg treatment showed similar leptin levels.
C Dimopoulou, J Schopohl, W Rachinger, M Buchfelder, J Honegger, M Reincke and G K Stalla
Transsphenoidal surgery (TSS) presents the treatment of choice for Cushing's disease (CD). Remission and recurrence rates vary dependent on tumor size, extension, adenoma visibility on magnetic resonance imaging, and neurosurgical expertise. Other than published from single-surgeon neurosurgical series so far, we have aimed to describe long-term remission and recurrence rates of CD in a series incorporating different neurosurgeons, trying to reflect care reality in the Munich Metropolitan Region, which is accommodated by three tertiary university and multiple, smaller neurosurgical centers.
We conducted a retrospective analysis of 120 patients who underwent first and 36 patients who underwent second TSS as treatment for CD between 1990 and 2012.
Patients were divided into three groups according to remission status. Potential risk factors for recurrence, pituitary function, and strategy in persistent disease were assessed.
Three outcome groups were identified according to remission status after first TSS (mean follow-up 79 months): remission, 71% (85/120), disease persistence, 29% (35/120), and disease recurrence, 34% (29/85) (mean time to recurrence 54 months). After second TSS (n=36, mean follow-up 62 months), we documented remission in 42% (15/36), disease persistence in 58% (21/36), and disease recurrence in 40% (6/15) (mean time to recurrence 42 months). Postoperative hypocortisolism after first, though not after second, TSS was associated with a lower risk of suffering disease recurrence (risk=0.72; 95% CI 0.60–0.88; exact significance (two-sided) P=0.035).
Our study shows higher recurrence rates of CD after first TSS than previously reported. Second TSS leads an additional 8% of the patients to long-term CD remission.
K. VON WERDER, J. SCHOPOHL, M. LOSA, J. ALBA LOPEZ, O.A. MÜLLER, J. PICHL, J. ROSENTHALER and E. DEL Pozo
M. LOSA, J. SCHOPOHL, R. HUSS, O. A. MÜLLER and K. VON WERDER
J. SCHOPOHL, G. WOLFRAM, CH. FREY, M. LOSA, R. HUBER, G. K. STALLA and K. VON WERDER
J. Schopohl, A. Hauer, T. Kaliebe, G. K. Stalla, K. von Werder and O. A. Müller
Abstract. ACTH secretion was studied in response to repetitive and continuous administration of human corticotropin releasing factor (CRF) in 14 healthy volunteers and 2 patients with secondary adrenal insufficiency. ACTH increases during repetitive CRF administration were within the same range in normal subjects independent of the intervals (60– 180 min) between the CRF pulses (100 μg iv). When CRF was infused continuously (100 μg/h for 3 h) after an initial CRF bolus injection (100 μg iv), ACTH and cortisol remained elevated during the infusion at a nearly constant level (ACTH: 60 ± 5 pg/ml; cortisol: 21.2 ± 1 μg/dl; x̄ ± se). A second CRF bolus injection at the end of the infusion did not lead to a significant further increase of ACTH and cortisol levels. This shows that there is no desensitisation or depletion of a ready releasable pool, as it is observed with other pituitary hormones after releasing hormone stimulation. Pulsatile administration of CRF in 2 patients with secondary adrenal insufficiency due to previous cortisol or glucocorticoid excess, respectively, revealed a blunted response to the first pulse which became normal after the following pulses. The latter could not be sustained until the next morning without CRF given overnight. These findings point to a hypothalamic defect being the cause of hypocortisolism after long-term cortisol suppression.