Markus Bettendorf

Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study

BACKGROUND Serum thyroid hormone concentrations decline transiently during critical illness and after surgical procedures. We investigated prospectively the endocrine and haemodynamic effects of tri-iodothyronine treatment after cardiopulmonary bypass operations in children with congenital cardiac malformations. METHODS We did a randomised, double-blind, placebo-controlled trial, in which 40 children (median age 0.6 years; range 2 days to 10.4 years) were randomly assigned placebo (saline) or one daily infusion of tri-iodothyronine (2 microg/kg bodyweight on day 1 after surgery and 1 microg/kg bodyweight on subsequent postoperative days up to 12 days after surgery. Before and 2 h, 24 h, and 72 h after the first infusion, plasma concentrations of thyroid hormones were measured by RIA, and systolic cardiac function was evaluated by echocardiography. During the postoperative course intensive-care measures were assessed by use of the therapeutic intervention scoring system. FINDINGS In all patients, postoperative plasma concentrations of thyrotropin, thyroxine, free thyroxine, tri-iodothyronine were abnormally low and plasma concentrations of reverse tri-iodothyronine were raised. After start of treatment, tri-iodothyronine was significantly higher in patients given tri-iodothyronine than in those receiving placebo, whereas thyrotropin, thyroxine, free thyroxine, and reverse tri-iodothyronine remained similar in the two groups. At discharge, thyroid hormones of all patients were within the normal range, but thyrotropin secretion increased to plasma concentrations higher than those seen before treatment. The mean change of cardiac index was significantly higher in children given tri-iodothyronine (20.4% [SD 19.6] vs 10.0% [15.2]; p=0.004). Systolic cardiac function improved most in patients given tri-iodothyronine after longer cardiopulmonary bypass operations. Overall, patients given tri-iodothyronine had significantly lower mean treatment scores. INTERPRETATION Treatment of children with tri-iodothyronine after cardiopulmonary bypass operations raises tri-iodothyronine plasma concentrations and improves myocardial function especially in patients with low postoperative cardiac output without adverse events, and without delaying postoperative recovery of thyroid function. Furthermore, tri-iodothyronine reduces the need for postoperative intensive care.

Transient Secondary Hypothyroidism in Children after Cardiac Surgery

Thyroid hormone status was assessed in 132 children with congenital heart defects undergoing cardiac surgery (median age 3.1 y; range 2 d to 16.2 y). Plasma TSH, thyroxine (T4), free thyroxine (fT4), triiodothyronine (T3), reverse triiodothyronine (rT3), thyroglobulin (Tg), and urinary iodine excretion were measured before and every other day after cardiac surgery (d 1-21). After surgery we observed strikingly low plasma concentrations of TSH (0.4 mU/L; 0.2-1.3), T3(0.6 nmol/L; 0.3-1.2), T4 (48.9 nmol/L; 12.9-82.4), fT4 (12.9 pmol/L; 5.1-19.3), and Tg (9.4 μg/L; 1.5-20.6), whereas rT3 plasma concentrations increased (0.13 pmol/L; 0.05-0.3; n = 40). The maximal postoperative changes of TSH and rT3 preceded changes of T3, T4, fT4, and Tg. Postoperative urinary iodine excretion increased significantly (n = 109). Thyroid hormone plasma concentrations were lowest after cardiopulmonary bypass operations and in patients treated with dopamine. In patients with postoperative T3 plasma concentrations less than 0.6 nmol/L (n = 52) the period of mechanical ventilation and intensive care treatment was significantly prolonged. Furthermore, the cumulative doses of inotropic and vasoactive catecholamines and furosemide were significantly higher in this patient group. Our results demonstrate transient secondary hypothyroidism in children after cardiac surgery that may contribute to postoperative cardiac and respiratory dysfunction and may delay recovery. Possible benefits of thyroid hormone replacement therapy need to be thoroughly examined.

Plasma Insulin-like Growth Factor I and IGF Binding Protein 3 Levels in Patients With Acute Cerebral Ischemic Injury

BACKGROUND AND PURPOSE The insulin-like growth factors (IGF) are synthesized in the brain and are involved in fetal brain development. An increased expression of IGF-I and IGF-II occurs in cerebral regions with neuronal damage after experimental hypoxic injury. Furthermore, the expression of mRNAs coding for IGF-I and the binding proteins IGFBP-2 and IGFBP-3 is augmented in response to unilateral ischemia in animal models. The secretory dynamics of IGF-I in human cerebral ischemia have not yet been investigated. METHODS Plasma IGF-I and IGFBP-3 were measured sequentially in 20 patients with acute ischemic stroke (within 24 hours and 3, 5, and 10 days thereafter). For analysis the patients were assigned to three groups according to the diameter of the infarct area as measured on CT scan: small (< 1.5 cm), moderate (> or = 1.5 cm and < or = 5 cm), and large (> 5 cm). Eight age-matched patients with nonvascular, neurological illnesses served as controls. RESULTS Plasma IGF-I and IGFBP-3 plasma concentrations after acute cerebral ischemia were strikingly lower than those in control subjects and healthy individuals reported in the literature. Plasma IGF-I levels in patients with large infarcts were significantly statistically lower than those in control subjects (P < .05), and plasma IGFBP-3 levels were significantly lower than those in control subjects on days 5 and 10. CONCLUSIONS IGF-I and IGFBP-3 plasma levels are decreased in patients after cerebral ischemia. After acute ischemic stroke, increased demand for growth factors, altered tissue distribution, and accelerated metabolic clearance rate or central inhibition of the somatotrophic axis may contribute to these low plasma concentrations. Growth factors such as IGF-I and IGFBP-3 may play an important role in the pathophysiology of acute cerebral ischemia, and growth factors may have a considerable effect on future therapeutic regimens.

LONGITUDINAL EVALUATION OF SALIVARY CORTISOL LEVELS IN FULL-TERM AND PRETERM NEONATES

The aim of the present study was to test the practicability of sequential cortisol determinations in saliva of low birth weight neonates and to evaluate the impact of systemic and inhaled glucocorticoid therapy on saliva concentrations of cortisol in preterm neonates with bronchopulmonary dysplasia (BPD). Salivary cortisol levels were measured by RIA in saliva samples from 10 full-term and 10 preterm healthy neonates and from 20 preterm neonates with BPD during systemic [dexamethasone (DEX); n = 10] or topical steroid therapy [budesonide (BUD); n = 10]. Saliva samples of each individual were collected on 3 consecutive days at 06.00, 12.00, 18.00 and 24.00 h. Cortisol levels in saliva ranged from 0.8 to 60.6 nmol/l (median 6.5 nmol/l) in full-term neonates, from 0.6 to 52.1 nmol/l (median 5.5 nmol/l) in preterm neonates, from 0.4 to 14.0 nmol/l (median 1.0 nmol/l) in preterm neonates treated with DEX and from 0.4 to 15.2 nmol/l (median 2.5 nmol/l) in preterm neonates treated with BUD. Autocorrelation analysis revealed a distinct endogenous cortisol rhythm in 2 of the 10 healthy full-term neonates and in 3 of the 10 healthy preterm neonates with a wavelength of 12–30 h. Salivary cortisol levels in preterm neonates treated with DEX or BUD were significantly lower than those measured in healthy preterm neonates. These results demonstrate that the measurement of salivary cortisol levels is a reliable and practicable way of assessing adrenal function in full-term and preterm neonates. This study also shows for the first time that some neonates display an endogenous cortisol rhythm which is not coupled to the exogenous day/night cycle. Furthermore, systemic and nebulized glucocorticoids suppress adrenal function in low-birth-weight neonates. After treatment these children should be closely monitored for potential adrenal insufficiency.

Lymphocytic hypophysitis with central diabetes insipidus and consequent panhypopituitarism preceding a multifocal, intracranial germinoma in a prepubertal girl

Abstract We report the clinical course of a prepubertal girl with central diabetes insipidus (DI) and consequent panhypopituitarism evolving over a period of 10 years due to lymphocytic hypophysitis and subsequent germinoma. Two years after the diagnosis of central DI was established, MRI revealed a thickened pituitary stalk. Later pituitary enlargement and increasing thickening of the pituitary stalk impinging on the optic chiasm required a trans-sphenoidal biopsy which disclosed active hypophysitis with lymphocytic infiltrates and necrosis. High dose dexamethasone treatment only temporarily halted the disease process. Therefore, stereotactic radiation therapy was performed as a rescue treatment and MRI findings almost reversed. However, the subsequent MRI showed multiple intracranial lesions identified histologically as a germinoma and a standard chemotherapy and radiation was performed. Conclusion The diagnosis of diabetes insipidus in children requires long-term follow up beyond the pubertal age in order to establish the underlying cause. In contrast to lymphocytic hypophysitis in adults, lymphocytic hypophysitis in prepubertal children may represent the first sign of a host reaction to an occult germinoma.

Metabolic Effects of Long-Term Growth Hormone Treatment in Prepubertal Children with Chronic Renal Failure and after Kidney Transplantation

To evaluate the metabolic effects of long-term treatment with recombinant human (rh) GH in short children with chronic renal failure (CRF), annual oral glucose tolerance tests (oGTT) during rhGH therapy for up to 5 y in 53 prepubertal children with CRF on conservative treatment, dialysis, and after renal transplantation were compared with that of 12 age-matched children treated with rhGH for idiopathic short stature. At the start of rhGH treatment, fasting values of glucose, insulin, glycosylated Hb A(HbA1C), triglycerides, cholesterol, glucose, and insulin responses during oGTT were significantly elevated in all patient groups compared with control subjects (p < 0.001). In the total population, fasting and 2-h postprandial glucose concentrations were inversely correlated with GFR and positively with age and methylprednisolone dosage in transplanted patients. Fasting insulin levels were positively correlated with body mass index and inversely with GFR. RhGH treatment was not associated with a change in fasting or stimulated glucose concentrations in any treatment group throughout the observation period. In contrast, serum insulin levels increased during the first treatment year in all groups, resulting in a more marked elevation of integrated insulin levels in transplant (1402 ± 179 pM) and dialysis (1025 ± 114 pM) patients compared with conservatively treated patients (829 ± 94 pM), and control subjects (719 ± 89 pM) (p < 0.01). Hyperinsulinemia persisted in all treatment groups for up to 5 y of follow-up. In conclusion, age, renal function, and obesity are the major independent predictors of glucose tolerance in children with CRF. Long-term rhGH treatment does not affect glucose tolerance, but aggravates the preexisting hyperinsulinemia in children with end-stage renal disease. In concert with the dyslipidemia of uremia, the rhGH-promoted hyperinsulinemia may contribute to the long-term risk for premature atherosclerosis in patients with childhood onset CRF.

Growth Analysis in Patients with 21-Hydroxylase Deficiency Influence of Glucocorticoid Dosage, Age at Diagnosis, Phenotype and Genotype on Growth and Height Outcome

Objective: To evaluate the impact of hydrocortisone dosage, age at diagnosis, compliance, genotype and phenotype on growth and height outcome in 21-hydroxylase-deficient patients. Methods: We analyzed 37 patients with 21-hydroxylase deficiency (17 had completed growth, 20 still growing). Final (FH)/predicted final height (pFH) and loss of height potential related to target height (TH) were calculated and the impact of 4 hydrocortisone (HC) dosage regimens on height outcome and growth velocities was evaluated. Mean FH SDS and pFH SDS were analyzed in accordance to age at diagnosis, compliance, genotype and phenotype. Results: Mean (FH SDS, pFH SDS) was –1.8 ± 1.06 SD, with 35.1% of all 37 patients exhibiting short stature. Doses >20 mg/m2/day during the first year and >15 mg/m2/day during age 1–5 and at puberty resulted in significantly lower FH SDS, pFH SDS and greater height losses. Age at diagnosis, compliance, genotype and phenotype played only a minor role in growth development. Conclusions: Hydrocortisone substitution in 21-hydroxylase-deficient patients should be kept at the lowest efficient level, if possible <20 during the first year and <15 mg/m2/day until age 5 and during puberty. Normal growth and not complete androgen suppression should be aimed for.

Prevalence of autoantibodies associated with thyroid and celiac disease in ullrich-turner syndrome in relation to adult height after growth hormone treatment

A prospective, multicenter study of patients with Ullrich-Turner syndrome (UTS) was conducted to estimate the prevalence of autoantibodies to tissue transglutaminase (tTg), thyroid stimulating hormone receptor (TSH-R), thyroglobulin (TG) and thyroid peroxidase (TPO) in relation to adult height after long-term growth hormone (GH) treatment. Out of 347 near-adult (> 16 years) patients with UTS from 96 German centers, whose longitudinal growth was documented within the Pharmacia International Growth Study (KIGS), 188 returned for a standardized follow-up visit at a median chronological age of 18.7 (16.0-23.6) years (bone age > 15 years). Serum samples of 120 patients were obtained for central measurements of TSH, thyroxine (T4) and free T4 and autoantibodies by standard immunoassays. Information regarding thyroid disease, karyotype and anthropometric data was extracted from the KIGS database. Thirty-six percent of the patients with UTS had positive TG and/or TPO autoantibodies and 4% had positive tTg autoantibodies, whereas 2% had positive TG and/or TPO autoantibodies as well as positive tTg autoantibodies. TSH-R autoantibodies were undetectable in all patients. The detection of autoantibodies was unrelated to a specific karyotype. Median height standard deviation scores (SDS, UTS) at start of GH treatment (0.43; -1.07, 1.85) and at follow-up (1.36; -0.11, 2.57) were comparable in all patients independent of their antibody status. The total deltaheight SDS, however, was higher in patients with negative autoantibody titers (1.08; -0.03, 2.25) compared to those with positive antibody titers (0.68; -0.44, 1.82; p < 0.01). Our study confirms the high prevalence of autoantibodies in patients with UTS predisposing them to autoimmune thyroid disease and celiac disease, and indicates for the first time that autoimmune pathologies may interfere with GH therapy and thus compromise final height. Therefore, medical care for patients with UTS should routinely include screening for these autoimmune disorders in order to assure early detection and appropriate treatment.

Three new 46,XX male patients: A clinical, cytogenetic and molecular analysis

BACKGROUND XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear. AIM To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRY results in a more masculinised phenotype. PATIENTS AND METHODS We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria. RESULTS Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Müllerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia. CONCLUSIONS In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.

Short-term, high-dose testosterone treatment fails to reduce adult height in boys with constitutional tall stature.

Abstract Height predictions based on three different methods (Bayley-Pinneau [BP], Tanner-Whitehouse Mark II [TW II], Roche-Wainer-Thissen [RWT]) were compared to adult heights in 19 males with constitutional tall stature previously treated with high-dose testosterone oenanthate for 6 months (group A) and 25 untreated tall males (group B). Their chronological ages (CA) at the initial evaluation of tall stature ranged from 12.1 to 16.6 years in group A and from 10.4 to 15.7 years in group B; at the time of assessment of adult height ages ranged from 18.0 to 26.5 years and from 18.4 to 25.1 years, respectively. Height measurements and predicted adult heights were expressed as height standard deviation scores (height SDS) for chronological age using the tables of Reinken and van Oost [14]. Height SDS in group A were 2.8 (range = 1.8–5.4) before testosterone treatment, 3.0 (range = 2.0–4.8) thereafter and finally 3.0 (range = 2.1–4.2) (P=NS) and in group B 2.7 (range = 0.5–4.3) and 2.4 (range = 1.3–3.5) (P=NS). A significant difference between adult height SDS and predicted height SDS according to BP was detected both in group A (3.0; range = 2.1–4.2 vs 3.6; range = 2.4–5.0; P≤0.004) and group B (2.4; range = 1.3–3.5 vs 3.0; range = 2.0–4.9; P≤0.0002), whereas no significant difference between adult height SDS and predicted height SDS according to TW II and RWT was found in either group. These data indicate that BP height predictions overestimated adult height in our patient group of treated and untreated males with constitutional tall stature. In contrast, the TW II and RWT methods were more accurate in predicting adult height in these patients, but also failed to demonstrate that testosterone therapy in boys with constitutional tall stature can be limited to a 6-month period in order to reduce adult height. Conclusion The widely used height prediction method of BP is inaccurate in boys with constitutional tall stature. High dose testosterone treatment fails to reduce adult height in these individuals when discontinued before complete closure of the epiphyses.