[Normoglycaemic ketoacidosis in pregnant patients with diabetes; early recognition is critical]. / Normoglykemische ketoacidose bij zwangere diabetici.

Diabetic ketoacidosis (DKA) during pregnancy is a rare but very serious complication that requires early recognition and treatment to prevent severe complications. Here we present three cases in which DKA occurred during normoglycaemia, demonstrating the importance of early recognition. In pregnancy, DKA can occur at lower blood glucose levels than usual due to several pregnancy-related factors, such as altered metabolism, increased insulin resistance, lower buffering capacity related to chronic hyperventilation and hunger. Symptoms that are common during pregnancy, such as vomiting, may be missed as a first sign of DKA. In patients with type 1 diabetes mellitus (especially those on continuous subcutaneous insulin infusion) insulin administration must never be discontinued, as this prevents lipolysis and ketone formation. Physicians and patients need to be aware of the risks and management of DKA in pregnancy.

It takes acid, rather than ice, to freeze glucose.

Plasma glucose levels provide the cornerstone of diabetes evaluation. Unfortunately, glucose levels drop in vitro due to glycolysis. Guidelines provide suitable conditions which minimize glycolysis, such as immediate centrifugation or the use of ice/water slurry storage containers. For obvious practical reasons, most laboratories use blood collection tubes containing glycolysis inhibitors. We describe the effect of a variety of commonly used blood collection tubes on in vitro stability of glucose. Furthermore, we looked at the validity of the assumption that glycolytic activity is minimal when blood is kept in an ice/water slurry. Sodium fluoride alone does not reduce in vitro glycolysis in the first 120 minutes after phlebotomy. Addition of citrate almost completely prevented in vitro glycolysis, but showed a positive bias (0.2 mmol/l) compared to control. This is partly due to a small drop in glucose level in control blood, drawn according to the current guidelines. This drop occurs within 15 minutes, in which glycolysis has been described to be minimal and acceptable. NaF-EDTA-citrate based test tubes provide the best pre-analytical condition available. Furthermore, glucose levels are not stable in heparinized blood placed in an ice/water slurry. We strongly advise the use of NaF-EDTA-citrate based test tubes in diabetes research.

Complications due to transfusion-related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury is an underdiagnosed and potentially lethal complication of blood transfusion. CASE: A patient underwent surgery because of an ectopic pregnancy. During surgery, blood products were administered and within minutes she developed pulmonary edema and hypotension. Treatment included mechanical ventilation, intravenous fluids, antihistamines, inotropic agents, cortisol, and diuretics. It took 4 days for the pulmonary edema to resolve and the patient to recover. Analysis of the donor plasma revealed human leukocyte antigen antibodies against an antigen of the patient. CONCLUSION: Although transfusion-related acute lung injury is usually self-limiting and most patients will recover spontaneously, the estimated mortality rate of 5-25% warrants prompt identification and adequate action.

[Diagnostic image (366). A man with haemorrhagic bullae after a fall]. / Diagnose in beeld (366). Een man met hemorragische bullae na een val.

A 71-year-old man with deep venous thrombosis treated with fenprocoumon presented after a trauma with a haematoma due to an INR > 8.0, and later with haemorrhagic bullae, due to venous obstruction.

Attenuated pulse size, disorderly growth hormone and prolactin secretion with preserved nyctohemeral rhythm distinguish irradiated from surgically treated acromegaly patients.

BACKGROUND: Radiation induces time-dependent loss of anterior pituitary function, attributed to damage of the pituitary gland and hypothalamic centres. The development of growth hormone deficiency (GHD) in irradiated acromegaly patients is not well defined. OBJECTIVE: Detailed analysis of spontaneous 24-h GH and prolactin (PRL) secretion in relation to other pituitary functions and serum IGF-I concentrations in an attempt to find criteria for GHD in acromegalic patients with a GH response < 3 microg/l during the insulin tolerance test (ITT). DESIGN: Plasma hormone profiles obtained by 10 min sampling for 24 h in postoperatively irradiated acromegalic patients, compared with patients cured by surgery only and matched healthy controls. SETTING/PARTICIPANTS: University setting. Fifteen subjects in each group. OUTCOME MEASURES: GH and PRL secretory parameters quantified by deconvolution, cluster, cosinor and approximate entropy (ApEn) analyses, IGF-I concentrations. RESULTS: Irradiation attenuated pulsatile secretion of GH and PRL, but total PRL secretion was unchanged. GH and PRL secretory regularity were diminished. Circadian timing remained intact. Pulsatile GH secretion and IGF-I were correlated (R = 0.30, P = 0.04). Criteria of pulsatile GH secretion = 12 microg/l/24 h and ApEn = 0.800 separated 12 of 15 irradiated patients from all others. CONCLUSION: Irradiated acromegaly patients with a subnormal GH response to ITT have very limited spontaneous GH secretion, with specific attenuation of the size of GH bursts and a highly irregular pattern, but with retained diurnal properties. These patients are thus likely GH-deficient and might benefit from GH replacement.

GH deficiency in patients irradiated for acromegaly: significance of GH stimulatory tests in relation to the 24 h GH secretion.

BACKGROUND: Radiotherapy for pituitary adenomas frequently leads to GH deficiency (GHD). The characteristics of GH secretion in GHD induced by postoperative radiotherapy for acromegaly are not known. HYPOTHESIS: In the long term, stimulated and spontaneous GH release is not different between patients with GHD treated by postoperative radiotherapy for acromegaly or for other pituitary adenomas. DESIGN/SUBJECTS: We compared the characteristics of basal and stimulated GH secretion in patients with GHD, who had previously received adjunct radiotherapy after surgery for GH-producing adenomas (n=10) vs for other pituitary adenomas (n=10). All patients had a maximal GH concentration by insulin tolerance test (ITT) of 3 microg/l or less, compatible with severe GHD. Mean time after radiation was 17 and 18.7 years, respectively. Stimulated GH release was also evaluated by infusion of growth hormone-releasing hormone (GHRH), GHRH-arginine and arginine, and spontaneous GH by 10 min blood sampling for 24 h. Pulse analyses were performed by Cluster and approximate entropy. OUTCOMES: There were no differences between both patient groups in stimulated GH concentrations in any test. Spontaneous GH secretion was not different between both patient groups, including basal GH release, pulsatility and regularity. Pulsatile secretion was lost in two acromegalic and three non-acromegalic patients. Insulin-like growth factor-I (IGF-I) was below -2 s.d. score in nine patients in each group. CONCLUSION: Acromegalic patients treated by surgery and postoperative radiotherapy with an impaired response to the ITT do not differ, in the long term, in GH secretory characteristics from patients treated similarly for other pituitary tumors with an impaired response to the ITT. The ITT (or the GHRH-arginine test) is therefore reliable in establishing the diagnosis of GHD in patients treated for acromegaly by surgery and radiotherapy.

Persistent diastolic dysfunction despite successful long-term octreotide treatment in acromegaly.

INTRODUCTION: This study was designed to evaluate potential reversibility of left-ventricular (LV) dysfunction in patients with acromegaly following long-term control of disease. It is unknown whether the cardiac changes induced by acromegaly can be reversed completely by long-term strict control of growth hormone excess by octreotide. PATIENTS AND METHODS: We compared LV systolic and diastolic function in inactive patients with acromegaly (n = 22), who were divided into patients with long-term control by octreotide (n = 14) and patients with long-term cure by surgery/radiotherapy (n = 8). We also assessed these parameters in patients with active acromegaly (n = 17). RESULTS: In patients with active acromegaly, systolic function at rest was decreased by 18% (P < 0.01), LV mass index increased by 40% (P < 0.04) and isovolumetric relaxation time increased by 19% (P < 0.01), compared with patients with inactive acromegaly. These parameters were not different between well-controlled and cured patients. Using tissue Doppler imaging, the ratio between early and late diastolic velocity (E'/A' ratio) was decreased in active, compared with inactive acromegaly (0.75+/-0.07 versus 1.24+/-0.15; P < 0.01). This E'/A' ratio was considerably higher in cured, compared with octreotide-treated, patients (1.75+/-0.41 versus 1.05+/-0.1; P < 0.01). CONCLUSION: Diastolic function is persistently and significantly more impaired in acromegalic patients with long-term control by octreotide than in surgically cured patients, which points to biological effects of subtle abnormalities in growth hormone secretion. Criteria for strict biochemical control of acromegaly should thus be reconsidered.

Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation.

IGF-I is a key factor in intrauterine development and postnatal growth and metabolism. The secretion of IGF-I in utero is not dependent on GH, whereas in childhood and adult life, IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GHRH receptor and GH receptor mutations. In a 55-yr-old male, the first child of consanguineous parents, presenting with severe intrauterine and postnatal growth retardation, microcephaly, and sensorineural deafness, we found a homozygous G to A nucleotide substitution in the IGF-I gene changing valine 44 into methione. The inactivating nature of the mutation was proven by functional analysis demonstrating a 90-fold reduced affinity of recombinantly produced for the IGF-I receptor. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. Nine of the 24 relatives studied carried the mutation. They had a significantly lower birth weight, final height, and head circumference than noncarriers. In conclusion, the phenotype of our patient consists of severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF-I in utero. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, is in agreement with the hypothesis that IGF-I secretion in childhood is mainly GH dependent. Remarkably, IGF-I deficiency is relatively well tolerated during the subsequent four decades of adulthood. IGF-I haploinsufficiency results in subtle inhibition of intrauterine and postnatal growth.

Quality of life in patients after long-term biochemical cure of Cushing's disease.

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.

Irregular and frequent cortisol secretory episodes with preserved diurnal rhythmicity in primary adrenal Cushing's syndrome.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

Octreotide long-acting repeatable and lanreotide Autogel are equally effective in controlling growth hormone secretion in acromegalic patients.

OBJECTIVE: Recently a new depot preparation of the long-acting somatostatin analogue, lanreotide Autogel was introduced for the treatment of acromegaly. Like octreotide long-acting repeatable (LAR), it has high binding affinity for the somatostatin receptor subtype SSTR 2 and less binding affinity for SSTR 5. We hypothesized that the ability to suppress growth hormone (GH) secretion in patients with acromegaly would be similar for these depot preparations. PATIENTS AND STUDY DESIGN: Seven patients (mean age+/-S.E.M. 48.4+/-7 years) on long-term octreotide LAR treatment at a monthly injection interval for a mean of 2.8 years were enrolled in the study. They underwent a GH secretory profile study with 10 min sampling for 24 h, 28 days after an injection. At 2, 4 and 6 weeks after the next injection fasting GH profiles (every 30 min for 3.5 h) and serum IGF-I measurements were measured. These investigations were repeated 12 months later, when the patients were on an individually titrated stable dose of lanreotide Autogel. RESULTS: Secretory characteristics and total 24 h GH secretion, estimated by deconvolution analysis of the 10 min 24 h plasma GH concentrations, did not show differences between these two long-acting somatostatin analogues. Both drugs were equally effective in GH and IGF-I suppression as measured at 2, 4 and also at 6 weeks following an injection. CONCLUSION: The efficacy of lanreotide Autogel and octreotide LAR was equal, notwithstanding that these drugs are administered in a different way and have different pharmacokinetics.