Context

Current guidelines on how to divide the daily cortisol substitution dose in patients with primary adrenal insufficiency (PAI) are controversial and mainly based on empirical data.

Objective

To assess how an equal dose of hydrocortisone given either four times daily or twice daily influence diurnal profiles of cortisol and ACTH, patient preferences and health related quality of life (HRQoL).

Design

Double blind, crossover.

Methods

Fifteen patients with PAI (6 women) were included. Capsules of hydrocortisone or placebo were given at 07:00, 12:00, 16:00 and 22:00 h in 4-week treatment periods: either one period with four doses (10+10+5+5 mg) or one period with two doses (20+0+10+0 mg). Diurnal profiles of cortisol and ACTH were collected and area under the curve (AUC) was calculated. Questionnaires were used to evaluate patient preferences and HRQoL.

Results

The four-dose regimen gave a higher serum cortisol before tablet intake in the morning (P = 0.027) and a higher 24-h-cortisol_AUC (P < 0.0001) compared with the two-dose period. In contrast a lower median plasma ACTH in the morning before tablet intake (P = 0.003) and a lower 24-h-ln(ACTH_AUC) were found during the four-dose period. The patients preferred the four-dose regimen (P = 0.03), and the HRQoL scores tended to be higher (high score indicates better HRQoL) for the four-dose period.

In summary a four-dose regimen gives increased availability of cortisol and an enhanced effect with a less elevated ACTH in the morning in comparison with a two-dose regimen but the effect on HRQoL remains inconclusive.

AIMS/HYPOTHESIS: The study aimed to compare the effects of a 2 year intervention with a low-fat diet (LFD) or a low-carbohydrate diet (LCD), based on four group meetings to achieve compliance. METHODS: This was a prospective randomised parallel trial involving 61 adults with type 2 diabetes consecutively recruited in primary care and randomised by drawing ballots. Patients that did not speak Swedish could not be recruited. The primary outcomes in this non-blinded study were weight and HbA(1c). Patients on the LFD aimed for 55-60 energy per cent (E%) and those on LCD for 20 E% from carbohydrate. RESULTS: The mean BMI and HbA(1c) of the participants were 32.7 ± 5.4 kg/m(2) and 57.0 ± 9.2 mmol/mol, respectively. No patients were lost to follow-up. Weight loss did not differ between groups and was maximal at 6 months: LFD -3.99 ± 4.1 kg (n = 31); LCD -4.31 ± 3.6 kg (n = 30); p < 0.001 within groups. At 24 months, patients on the LFD had lost -2.97 ± 4.9 kg and those on LCD -2.34 ± 5.1 kg compared with baseline (p = 0.002 and p = 0.020 within groups, respectively). HbA(1c) fell in the LCD group only (LCD at 6 months -4.8 ± 8.3 mmol/mol, p = 0.004, at 12 months -2.2 ± 7.7 mmol/mol, p = 0.12; LFD at 6 months -0.9 ± 8.8 mmol/mol, p = 0.56). At 6 months, HDL-cholesterol had increased with the LCD (from 1.13 ± 0.33 mmol/l to 1.25 ± 0.47 mmol/l, p = 0.018) while LDL-cholesterol did not differ between groups. Insulin doses were reduced in the LCD group (0 months, LCD 42 ± 65 E, LFD 39 ± 51 E; 6 months, LCD 30 ± 47 E, LFD 38 ± 48 E; p = 0.046 for between-group change). CONCLUSIONS/INTERPRETATION: Weight changes did not differ between the diet groups, while insulin doses were reduced significantly more with the LCD at 6 months, when compliance was good. Thus, aiming for 20% of energy intake from carbohydrates is safe with respect to cardiovascular risk compared with the traditional LFD and this approach could constitute a treatment alternative. TRIAL REGISTRATION: ClinicalTrials.gov NCT01005498 FUNDING: University Hospital of Linköping Research Funds, Linköping University, the County Council of Östergötland, and the Diabetes Research Centre of Linköping University.

Context: Data on bone mineral density (BMD) are lacking in adults with childhood onset (CO)-craniopharyngioma (CP) with hypothalamic damage from the tumor. In patients with CO GH deficiency, BMD increases during GH treatment. Objective: The aims were to evaluate BMD in adults with CO-CPs on complete hormone replacement, including long-term GH and to evaluate the impact of hypothalamic damage on these measures. Design and participants: BMD (dual-energy X-ray absorptiometry), markers of bone turn over, physical activity and calcium intake were assessed in 39 CO-CP adults (20 women), with a median age of 28 (17-57) years, in comparison with matched population controls. Results: Late puberty induction was recorded in both genders, but reduced androgen levels in females only. Only CP women had lower BMD (PZ0.03) at L2-L4, and reduced Z-scores at femoral neck (P=0.004) and L2-L4 (P=0.004). Both genders had increased serum leptin levels (P=0.001), which significantly correlated negatively with BMD at L2-L4 (P=0.003; r=-0.5) and 45% of CP women had Z-score levels less than= -2.0 S.D. Furthermore, 75% of those with a Z-score less than= -2.0 S.D. had hypothalamic involvement by the tumor. Calcium intake (P=0.008) and physical activity (P=0.007) levels were reduced in CP men only. Levels of ostecalcin and crossLaps were increased in CP men only. Conclusions: Despite continuous GH therapy, low BMD was recorded in CO-CP females. Insufficient estrogen and androgen supplementation during adolescence was the main cause, but hypothalamic involvement with consequent leptin resistance was also strongly associated with low BMD in both genders.

Context: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile.

Objective: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.

Design and Setting: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.

Patients: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).

Intervention: The same daily dose of hydrocortisone was administered as OD dual-release or TID.

Main Outcome Measure: We evaluated cortisol pharmacokinetics.

Results: Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).

Conclusion: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.

Objective. Patients with inflammatory bowel disease (IBD) often have low iron stores or anaemia. There is controversy about whether iron should be supplemented orally or intravenously (i.v.). The purpose of this study was to investigate whether treatment with intravenous iron is superior to treatment with oral iron. The primary end-points were response and remaining anaemia at the end of treatment (EOT).

Material and methods. Ninety-one patients with IBD and anaemia (B-Hb <115 g/L) were randomized to oral iron sulphate (n=46) or intravenous iron sucrose (n=45) treatment for 20 weeks.

Results. Forty-three patients in the intravenous iron group completed the study compared to 35 patients in the oral iron group (p=0.0009). Only 22 patients (48%) tolerated the prescribed oral dose, and 52% reduced the dose or withdrew from treatment because of poor tolerance. At EOT, 47% patients in the oral iron group increased their B-Hb by ≥20 g/L, compared with 66% in the intravenous iron group (p=0.07). In the oral iron group, 41% still had anaemia versus 16% of the patients in the intravenous iron group (p=0.007), and 22% versus 42% reached their reference B-Hb level (p=0.04). Treatment with intravenous iron sucrose improved iron stores faster and more effectively than oral iron (p=0.002). Under treatment with intravenous iron, 74% of the patients had no anaemia and normal S-ferritin levels (>25 µg/L) at EOT compared with 48% of patients receiving oral iron (p=0.013).

Conclusions. Treatment with intravenous iron sucrose is effective, safe, well tolerated and superior to oral iron in correcting haemoglobin and iron stores in patients with IBD.

Objective It was hypothesized that increased bone mineral density of the medial proximal tibia would precede or coincide with the development of more severe cartilage changes after meniscectomy.

Methods In a rabbit knee model, mineral density of subchondral bone and changes of articular cartilage were monitored 13 to 40 weeks after medial meniscectomy or a sham operation.

Results Both procedures resulted in a decrease of bone mineral density, especially of the medial proximal tibia, which persisted up to 40 weeks (P< 0.02–0.0007). Meniscectomy induced cartilage changes typical for osteoarthrosis (P< 0.009), which progressed over time on the posterior aspect of the medial tibial plateau (P< 0.009), which is physiologically covered by the meniscus, but the procedure also induced iatrogenic changes which were located mainly on the anterior aspect of the concerned compartment, and which did not progress or develop to osteoarthrosis.

Conclusions The data suggest that the cartilage changes after meniscectomy in this animal model are caused by the surgical trauma, subsequent limb misuse, and altered load distribution, and initially associated by a decrease not an increase in bone mineral density of the proximal tibia. Moreover, the cartilage changes progressed without a simultaneous increase of the bone mineral density at corresponding sites.

Many women with typical anginal chest pain have normal coronary angiograms, which may be due to altered endothelial function. We evaluated the endothelial markers cyclic GMP (cGMP) and immunoreactive endothelin (ir-ET) regarding presence of coronary atherosclerosis in women with clinical signs of unstable coronary artery disease (CAD). Plasma levels of cGMP and ir-ET were determined in 118 patients and 84 controls. Ischaemia was evaluated at an exercise test. Of the patients 20% had normal vessels, 14% insignificant CAD and 66% significant stenosis at coronary angiography. Mean (95% CI) concentration of cGMP (nmol/l) was higher in patients than in controls (5.05 (4.53; 5.58) vs. 3.79 (3.34; 4.23)). Separating patients according to daily intake of nitroglycerin, only patients with this medication had significantly higher cGMP level (5.73 (4.88; 6.58)), whereas the difference between those without (4.35 (3.76; 4.94)) and controls disappeared. Patients with ischaemia at exercise test had higher cGMP level than those without (6.01 (5.13; 6.88) vs. 4.30 (3.66; 4.94)), even after adjusting for nitroglycerin treatment. ir-ET (pmol/l) was lower in patients with normal vessels than patients with coronary atherosclerosis (0.83 (0.78; 0.88) vs. 0.98 (0.92; 1.04)) and than the control group (0.91 (0.87; 0.94)). The difference between the control group and patients with atherosclerosis was also significant. Patients with unstable CAD and long-term nitroglycerin treatment have increased cGMP level. Patients with exercise-induced ischaemia have higher cGMP level than those without, irrespective of nitroglycerin treatment, which may reflect a general compensatory mechanism. Patients with normal vessels have low level of ir-ET, indicating different mechanisms for ischaemia/angina in these patients compared with patients with atherosclerosis.

Background.The contribution of plasma lipids to cardiovascular risk is usually evaluated by measuring plasma concentrations of total cholesterol, triglycerides and HDL cholesterol, and calculating LDL cholesterol concentration. We investigated plasma concentrations of apolipoproteins and lipoprotein particles in women with unstable coronary artery disease (CAD) to evaluate whether these, better than the routine lipid status, could differentiate women with and without coronary atherosclerosis.

Methods. Blood samples for lipid analyses were collected from 119 angiographically examined postmenopausal 49–79-year-old women with unstable CAD, and from 101 age-matched controls. Mean plasma concentrations were compared and the discriminatory ability of the different variables were tested using receiver operating characteristics (ROC).

Results. At coronary angiography 19% had normal vessels and 81% had coronary atherosclerosis. A disturbed triglyceride metabolism was the most pronounced lipid abnormality in women with unstable CAD and coronary atherosclerosis. ROC showed that none of the evaluated variables had a particularly high discriminatory power regarding unstable CAD or coronary atherosclerosis. The ratio cholesterol/HDL cholesterol was best with an ROC area of 0.79. Furthermore, the newer lipid variables, i.e. lipoprotein particles and apolipoproteins, were no better than the traditional variables.

Conclusion. Lipoprotein changes reflecting a disturbed triglyceride metabolism are most pronounced in women with unstable CAD and coronary atherosclerosis. Lipoprotein particles and apolipoproteins alone were no better than lipids and lipoproteins in separating women with from those without coronary atherosclerosis. Our study does not support the measurement of apolipoproteins and lipoprotein particles on the basis of diagnostic accuracy alone.

Population-based reference values for IGF-I and IGF-binding protein-1 (IGFBP-1) have been established. One hundred and one women and the same number of men, 20–70 years old, were randomly selected from the population registry in the community of Linköping. Participation rate was 67%. Venous blood was drawn in the fasting state. Serum IGF-I was measured by RIA after acid-ethanol extraction and IGFBP-1 was determined by ELISA. IGF-I levels did not differ between genders and the decline with age was similar in men and women (men: Y=366–3·28×age (years), r =−0·61, P<0·0001; women: Y=386–3·49×age, r =−0·57, P<0·0001, P=0·4 for difference in slope). There were negative correlations between IGF-I and plasma lipids and blood pressure in both genders, but none was independent of age. Serum angiotensin-converting enzyme activity correlated positively with IGF-I in men independently from age (r =0·21, P=0·01). The distribution of IGFBP-1 was positively skewed and it was higher in women than in men (5·9±4·8 μg/l and 4·0±3·3 μg/l respectively; Mann–Whitney, P=0·002). In men and in the women not taking oestrogen, IGFBP-1 correlated positively with age (Spearman rank correlation (Spearman): men: r=0·32, P=0·002; women: r=0·24, P=0·03). C-peptide correlated negatively (Spearman: men: r =−0·38, P=0·002; women: r =−0·49, P<0·000) and sex hormone binding globulin positively with IGFBP-1 (Spearman: men: r=0·50, P<0·0001; women: r =0·55, P<0·0001).

Traumatisk hjärnskada (traumatic brain injury, TBI) är en av de vanligaste orsakerna till död och nedsatt funktion hos människor i arbetsför ålder.

Patienter som överlever svåra skallskador utgör en växande patientkategori inom dagens sjukvård.

På senare år har det aktualiserats att allvarligt skalltrauma kan ge skador i hypofys–hypotalamusregionen.

Det är angeläget att dessa patienter utreds för eventuell hypofyssvikt så att hormonell substitutionsterapi kan inledas om endokrin insufficiens fastställs. Detta kan förhoppningsvis underlätta efterföljande rehabilitering och därmed förbättra pro­gnosen.

Vi presenterar här ett förslag till riktlinjer för utvärdering av hypofysfunktionen hos TBI-patienter. Samtidigt vill  vi informera en bredare läsekrets om TBI-begreppet.

Introduction

Pulmonary carcinoids associated with ectopic adrenocorticotropic hormone secretion have a good prognosis if histological examination shows typical pulmonary carcinoid and low proliferation, whereas a poor outcome is linked to atypical pulmonary carcinoid and high proliferation. Here we describe the diagnostic challenges to find the tumor in Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone secretion in two cases with an atypical and a typical pulmonary carcinoid, respectively.     

Case presentation

A 63-year-old Caucasian woman presented with aggressive clinical features related to Cushing’s syndrome, having very high levels of urinary cortisol and circulating adrenocorticotropic hormone and cortisol. Magnetic resonance imaging showed no pituitary tumor, and bilateral inferior petrosal sinus sampling revealed no central peripheral ratio of adrenocorticotropic hormone. Computed tomography and ¹¹¹Indium-pentetreoide somatostatin receptor scintigraphy could not visualize any ectopic tumor. The patient was referred for an ¹¹C-5-hydroxytryptophan positron emission tomography, and a small 8mm nodule in her left lung was found. The tumor was removed via a lateral thoracic incision and wedge excision. The histological examination showed an atypical carcinoid with Ki-67 index of 9 to 10%, and an additional lobectomy was performed.     

The second patient, a 22-year-old Caucasian man, also presented with aggressive Cushing’s syndrome, with very high urinary cortisol levels and increased circulating cortisol as well as adrenocorticotropic hormone levels. A magnetic resonance imaging scan of the pituitary showed no tumor, whereas a 12×9×14mm tumor was detected in the right lung on the primary computed tomography scan and no further investigation was performed. The tumor was removed via a lateral thoracic incision and wedge excision. A typical carcinoid with Ki-67 index of 1 to 2% was found and no further surgery was performed.     

After surgical removal, the biochemical disturbances resolved and significant clinical improvement were achieved in both patients after 24 months of follow up.     

Conclusions

Diagnostic evaluation time is limited due to the aggressive course in ectopic adrenocorticotropic hormone-dependent Cushing’s syndrome. We suggest that ¹¹C-5-hydroxytryptophan positron emission tomography could be considered early as a secondary diagnostic tool when primary computed tomography and/or magnetic resonance imaging scans fail to show any tumor.

A dominance of Th2 cytokine pattern is associated with allergic diseases, whereas a Th1 pattern has been reported in autoimmune type 1 diabetes (T1D). The Th1/Th2 paradigm has led to the interest in the relationship between these diseases. To investigate the association between atopic diseases, asthma and occurrence of T1D-related β-cell autoantibodies in children, we studied 7208 unselected 2.5-yr-old children from the All Babies in Southeast Sweden (ABIS) cohort. The ABIS cohort includes 17 055 (78.3% out of all 21 700) children born from October 1997 to October 1999, and followed prospectively with regular biological samples and questionnaires, at birth, at 1 and 2.5 yr. Risk factors for development of β-cell autoantibodies at the age of 2.5 yr were type of domiciliary, domestic animals (cat and dog) and getting a new brother/sister during first year of life. Maternal smoking during pregnancy [odds ratio (OR) 1.6] and heavy smoking at home (>10 vs. ≤10 cigarettes) implied risk for tyrosine phosphatase autoantibodies (IA-2A) (OR 2.9). Wheezing during the first year of life implied risk for glutamic acid decarboxylase autoantibodies (GADA) (OR 1.9) and double positivity for GADA and IA-2A (OR 9.1). Rash on several locations (at least three times during 12 months) (OR 1.7) as well as allergic symptoms related to fur-bearing animals (OR 2.7) implied risk for IA-2A. Food allergy against egg, cow-milk, fish, nuts/almonds (one or in combination) implied risk for GADA and IA-2A (OR 4.5). In a regression model wheezing during first year of life remained as a risk factor for GADA [OR 2.0, confidence interval (CI) 1.1–3.8; p = 0.031] and both GADA and IA-2A (OR 10.7, CI 3.9–29.4; p = 0.000). We conclude that allergic symptoms are associated with the development of T1D-related autoantibodies during the first years of life.