Jeanette Wahlberg

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation

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.

Deaths Among Adult Patients With Hypopituitarism : Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality

CONTEXT Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. OBJECTIVE To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. DESIGN AND METHODS All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. MAIN OUTCOME MEASURES Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. RESULTS An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. CONCLUSION Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

Short duration of breast-feeding as a risk-factor for β-cell autoantibodies in 5-year-old children from the general population

Breast-feeding has been suggested to have a protective effect against the development of type 1 diabetes. In the present study, we investigated the relation between duration of breast-feeding and beta-cell autoantibodies in 5-year-old non-diabetic children who participated in a prospective population-based follow-up study (the All Babies in Southeast Sweden study). Autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tryosine phosphatase-like IA-2 (IA-2A) were measured by radiobinding assays. A short duration of total breast-feeding was associated with an increased risk of GADA and/or IAA above the ninety-fifth percentile at 5 years of age (OR 2.09, 95% CI 1.45, 3.02; P<0.000) as well as with an increased risk of IAA above the ninety-fifth percentile at this age (OR 2.89, 95% CI 1.81, 4.62, P<0.000). A short duration of exclusive breast-feeding was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 2.01, 95% CI 1.08, 3.73; P=0.028) as well as with an increased risk of IA-2A above the ninety-ninth percentile (OR 3.50, 95% CI 1.38, 8.92, P=0.009) at 5 years of age. An early introduction of formula was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 1.84, 95% CI 1.01, 3.37; P=0.047) at 5 years of age. The positive association between a short duration of both total and exclusive breast-feeding, as well as an early introduction of formula, and positivity for beta-cell autoantibodies in children from the general population suggest that breast-feeding modifies the risk of beta-cell autoimmunity, even years after finishing breast-feeding.

Dietary risk factors for the emergence of type 1 diabetes-related autoantibodies in 21/2 year-old Swedish children.

We studied dietary risk factors by analysing a questionnaire administered at birth, 1 year and 2(1/2) years of age, as well as the level of glutamic acid decarboxylase autoantibodies (GADA) and tyrosine phosphatase autoantibodies (IA-2A), in 7208 2(1/2)-year-old children from the All Babies in Southeast Sweden cohort, using the 95th percentile cut-off for autoantibodies to identify children at risk of type 1 diabetes. A total of 657 children had either IA-2A (n 360) or GADA (n 335), and thirty-eight children had both GADA and IA-2A. In univariate analysis, male gender and maternal coeliac disease implied a risk of possessing IA-2A. Maternal type 2 diabetes, a high consumption of fresh cows milk at the age of 1 year and a late introduction of gluten were associated with a risk of GADA. Early cessation of breast-feeding (< 2 months of age) was associated with a risk of the simultaneous occurrence of both IA-2A and GADA. In logistic regression analysis, a high consumption of milk at the age of I year (odds ratio 2.6)represented a risk for GADA, and maternal coeliac disease (odds ratio 2.9) represented a risk for IA-2A. The combination of an early introduction of cows milk formula and a late introduction of gluten-containing food gave an odds ratio of 6.0 for positivity for at least one autoantibody at 1 and 21 years of age. The induction of autoantibodies by the age of 2(1/2) years has a male preponderance and is more common in children with maternal type 2 diabetes or maternal coeliac disease. Dietary risk factors for the induction of beta-cell autoantibodies in 21-year-old children are a short duration of breast-feeding, an early introduction of cows milk formula and a late introduction of gluten, as well as a high consumption of milk at the age of I year.

A randomized, double‐blind, crossover study comparing two‐ and four‐dose hydrocortisone regimen with regard to quality of life, cortisol and ACTH profiles in patients with primary adrenal insufficiency

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.

Vaccinations May Induce Diabetes‐Related Autoantibodies in One‐Year‐Old Children

Abstract: Vaccinations have been discussed as one among many environmental candidates contributing to the immune process that later may lead to type 1 diabetes. ABIS (All Babies in Southeast Sweden) is a prospective cohort study following a nonselected birth cohort of general population. In a randomly selected sample collection from 4400 children, GADA and IA‐2A have been determined at the age of 1 year. The information on vaccinations was collected from questionnaires answered by the parents and was related to β cell autoantibodies. When studying the induction of autoantibodies using the autoantibody level of 90th percentile as cutoff level, hemophilus influenza B (HIB) vaccination appeared to be a risk factor for IA‐2A [OR 5.9 (CI 1.4‐24.4; p= 0.01)] and for GADA [OR 3.4 (CI 1.1‐10.8; p= 0.04)] in logistic regression analyses. Furthermore, the titers of IA‐2A were significantly higher (p < 0.01 in Mann‐Whitney test) in those children who had got HIB vaccination. When 99th percentile was used as cutoff to identify the children at risk of type 1 diabetes, BCG vaccination was associated with increased prevalence of IA‐2A (p < 0.01). We conclude that HIB vaccination may have an unspecific stimulatory polyclonal effect increasing the production of GADA and IA‐2A. This might be of importance under circumstances when the β cell‐related immune response is activated by other mechanisms.

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

Objective The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). Design Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. Methods Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). Results In stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. Conclusions This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Environmental factors related to the induction of beta-cell autoantibodies in 1-yr-old healthy children.

Abstract:  We studied environmental risk factors which might contribute to the development of beta‐cell autoantibodies in healthy children. Here, we investigated 6000 randomly selected children from the large All Babies in Southeast Sweden (ABIS) cohort, including 17 055 newborns recruited between 1997 and 1999. Questionnaires at birth and at 1 yr of age and the levels of autoantibodies to glutamic acid decarboxylase (GADA) and autoantibodies to tyrosine phosphatase (IA‐2A) at 1 yr of age were analyzed. The 99th percentile cutoff for autoantibodies was proposed to identify children at risk of type 1 diabetes (T1D) and the 90th percentile cutoff to identify children in whom beta‐cell autoimmunity has been induced. Using the 90th percentile cutoff level, 1156 children had either IA‐2A (n = 574) or GADA (n = 582), while 126 children had both GADA and IA‐2A. When the 99th percentile cutoff level was used, 114 children had either IA‐2A (n = 57) or GADA (n = 57), and six children had both GADA and IA‐2A. In logistic regression analysis, celiac disease in grandparents [odds ratio (OR) 2.2] and maternal gastrointestinal infection (OR 1.1) represented a risk for simultaneous occurrence of both IA‐2A and GADA above the 90th percentile. Birth in spring (March to May) (OR 1.5) and male gender (OR 1.3) were risk factors for induction of IA‐2A. Mothers low education represented a risk for induction of IA‐2A (OR 1.5) and GADA (OR 1.4). T1D in first‐degree relatives increased the risk for beta‐cell autoimmunity above the 99th percentile (OR 2.6), whereas type 2 diabetes in grandparents was associated with GADA (OR 2.1). Exposure to cows milk formulas <2 months of age implied an OR of 2.9 for IA‐2A above the 99th percentile.

Progression to type 1 diabetes and autoantibody positivity in relation to HLA‐risk genotypes in children participating in the ABIS study

Background:  Autoantibodies against beta‐cell antigens together with human leukocyte antigen (HLA)‐risk genotypes are used as predictive markers for type 1 diabetes (T1D). In this study, we have investigated the role of HLA‐risk and ‐protective genotypes for development of beta‐cell autoantibodies and progression to T1D in healthy children.

Asthma and allergic symptoms and type 1 diabetes-related autoantibodies in 2.5-yr-old children

Wahlberg J, Vaarala O, Ludvigsson J, for the ABIS Study Group. Asthma and allergic symptoms and type 1 diabetes‐related autoantibodies in 2.5‐yr‐old children.