Idiopathic isolated adrenocorticotropic hormone deficiency: a systematic review of a heterogeneous and underreported disease.

Isolated adrenocorticotropic hormone deficiency (IAD) is considered to be a rare disease. Due to the nonspecific clinical presentation, precise data on the prevalence and incidence are lacking. In this systematic review, we aimed to analyse the clinical characteristics, association with autoimmune diseases, and management of acquired idiopathic IAD cases. A structured search was conducted after developing a search strategy combining terms for acquired (idiopathic) IAD. Articles describing an adult case with a diagnosis of ACTH deficiency using dynamic testing, no deficiency of other pituitary axes, and MRI of the brain/pituitary protocolled as normal, were included. Exclusion criteria were cases describing congenital IAD, cases with another aetiology for IAD, and articles where full text was not available. In total 42 articles were included, consisting of 85 cases of acquired idiopathic IAD. Distribution by sex was approximately equal (F:M; 47:38). Lethargy was the most common presenting symptom (38%), followed by weight loss (25%), anorexia (22%), and myalgia/arthralgia (12%). Eight cases (9.5%) presented with an Addison crisis. 31% of cases had an autoimmune disease at diagnosis of which Hashimoto hypothyroidism was the most frequent. Data about follow-up was scarce; dynamic testing was repeated in 4 cases of which 2 showed recovery of the adrenal axis. We report the largest case series of acquired idiopathic IAD to date. Our systematic review highlights the lack of a clear definition and diagnostic work-up. Based on the findings in this review a proposition is made for a flowchart to diagnose acquired idiopathic IAD.

Prediction of exocrine and endocrine insufficiency after pancreaticoduodenectomy using volumetry.

Objectives: The aim of this study is to evaluate the use of pancreatic volumetric assessment to predict exocrine and endocrine insufficiency after pancreaticoduodenectomy.Methods: Thirty-seven patients who underwent pancreaticoduodenectomy were included in the study. Endocrine function was assessed in all patients without a history of diabetes using an oral glucose tolerance test. A 13C-labeled mixed triglyceride (MTG) breath test evaluated exocrine function before and after resection. Volumetric measurements were performed on CT or MRI.Results: The volumetric measurements could not predict pre- or postoperative diabetes. Moreover, the resected volume was significantly lower in patients who developed diabetes after resection. Comparing patients with a normal and disturbed postoperative MTG, postoperative volumes and parenchymal thickness were significantly different. The parenchymal thickness on postoperative imaging is withheld as a predictive factor (OR = .85 [95% CI .71-1.01], p = .049). The best cutoff value to predict exocrine insufficiency is a parenchymal thickness of less than 11.4 mm (AUC = .76, p = .025, sensitivity = 88.9%, specificity = 70.0%).Conclusions: Pancreatic remnant volumetry and parenchymal thickness measurement after pancreaticoduodenectomy are correlated with exocrine insufficiency, but with limited predictive value. None of the preoperative measurements are withheld to predict postoperative exocrine function. Pre- and postoperative volumetry appear to have no use in predicting postoperative diabetes.

Not performing an OGTT results in significant underdiagnosis of (pre)diabetes in a high risk adult Caucasian population.

OBJECTIVE: Type 2 diabetes (T2DM) is known to be underdiagnosed. Tests for diagnosis include fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) and HbA1c. HbA1c can be tested in non-fasting conditions. Therefore, general practitioners almost no longer execute OGTT's. We evaluated the performance of OGTT versus HbA1c in a population consisting of overweight and obese subjects, which can be considered a 'high risk' population. RESEARCH DESIGN AND METHODS: A total of, 1241 overweight and obese subjects without a history of diabetes (male/female: 375/866, age 44±13 years, body mass index 38.0±6.1 kg m-2) were tested for glucose tolerance status using FPG, OGTT and HbA1c. RESULTS: Exactly, 46.8% were found to have prediabetes and 11.9% were newly diagnosed with T2DM (male/female=18.9/8.9%) using ADA criteria. Testing only HbA1c would have resulted in 78 subjects being diagnosed with T2DM, but 47.3% of newly diagnosed patients would have been missed if OGTT would not have been done. Exactly 581 subjects were diagnosed with prediabetes, 1.4% subjects had impaired fasting glucose (IFG) 30.5% had impaired glucose tolerance (IGT), 5.1% subjects had a combined IFG+IGT, and 9.8% had an isolated elevated HbA1c (5.7-6.4%). Of the 581 subjects with prediabetes, 257 had an HbA1c <5.7%. Therefore, 44.2% subjects would have been missed when OGTT would not have been done. CONCLUSION: In a population with only overweight and obese adult subjects, 46.8% were diagnosed with prediabetes and 11.9% were newly diagnosed with diabetes. Exactly, 5.6 and 20.7% of total population met the diagnostic criteria of the OGTT for diabetes and prediabetes, respectively, but did not meet the diagnostic criteria of the HbA1c. These data suggest that not performing an OGTT results in significant underdiagnose of T2DM in an overweight and obese adult population.

Screening for type 2 diabetes mellitus in overweight and obese subjects made easy by the FINDRISC score.

AIM: To evaluate the use of the FINDRISC score in an overweight and obese population to predict glucose status. METHODS: In 651 overweight/obese subjects (M/F: 193/458, age 43±13 y, BMI 38.2±6.1kg/m(2)) glucose status was tested using OGTT and HbA1c. Furthermore, the FINDRISC questionnaire and CT visceral fat (VAT) and subcutaneous fat (SAT) were examined. RESULTS: Exactly 50.4% were found to have prediabetes and 11.1% were newly diagnosed with type 2 diabetes (T2DM) (M/F=22.2/8.8%). Subjects without T2DM had a FINDRISC score of 11±3, those with pre-DM 13±4, and subjects with de novo T2DM 15±5. The aROC of the FINDRISC for detecting T2DM was 0.76 (95% CI 0.72-0.82), with 13 as cutoff point. The FINDRISC score correlated with VAT (r=0.34, p<0.001) and VAT/SAT ratio (r=0.39, p<0.001). The aROC of the FINDRISC to detect excess VAT was 0.79 (95%CI 0.72-0.84). CONCLUSIONS: In a large group of overweight and obese subjects, 50.4% were found to have pre-DM and 11.1% were newly diagnosed with T2DM. The FINDRISC score increased with worsening of glucose tolerance status and proved to be an independent predictor of T2DM status, as did HOMA-B, HOMA-S and VAT. The FINDRISC can also function as a good tool to predict visceral obesity.

[Levels of target achievement for major modifiable cardiovascular risk factors in Belgium]. / Niveaux d'atteinte des valeurs cibles thérapeutiques pour des facteurs majeurs modifiables du risque cardiovasculaire en Belgique.

Cardiovascular disease (CVD) is the main cause of premature mortality in Europe. The burden of CVD could be reduced by controlling the major modifiable CVD risk factors (dyslipidaemia, arterial hypertension, hyperglycaemia, smoking, and physical inactivity) through lifestyle and dietary changes and appropriate drug therapies. The objective of this article is to assess the level of target achievement for key modifiable CVD risk factors in Belgium by referring to the data from four recent studies. The overall results show that the main CVD risk factors are poorly controlled in patients with established CVD and in patients at high CVD risk. Therapeutic targets may be incompletely reached because of the suboptimal implementation of European guidelines for CVD prevention in routine clinical practice (insufficient lifestyle and dietary adaptations; poor applications of drug therapy to control blood pressure, dyslipidaemia and hyperglycaemia) or because of the insufficient efficacy of currently available treatment options in some patients. This review provides clear and updated evidence for non-target achievement for all major risk factors, with four different study designs and inclusion criteria; it highlights the need for a more comprehensive and intensive application of recommendations of the European guidelines for CVD prevention in Belgium.

Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost-effective and age-independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients.

In first-degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA-2) and zinc transporter 8 (ZnT8) antibody status (IA-2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA-2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow-up of 6444 siblings and offspring aged 0-39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA(+) , GADA(+) , IA-2A(+) and/or ZnT8A(+) relatives (6·1%). After a median follow-up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0-9, 10-19 and 20-39 years) progression to diabetes was significantly quicker in the presence of IA-2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age-independent in IA-2A(+) and/or ZnT8A(+) relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10-39 years), screening for IA-2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for ≥ 2 antibodies among IAA, GADA, IA-2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA-2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost-effective to select participants for intervention trials than conventional screening.

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass.

AIMS/HYPOTHESIS: The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3. METHODS: Eighty patients, aged 12-39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n=40) or ChAglyCD3 (n=40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg(-1)day(-1)) over 48 months was chosen as primary endpoint and compared in 31 placebo-and 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively. RESULTS: Treatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48 months (+0.09 vs +0.32 U kg(-1)day(-1) in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48 months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27 years old, antibody treatment preserved initial beta cell function for 36 months (vs >80% decline within 24 months in the placebo subgroup <27 years old), resulted in lower HbA1c concentrations and tended to reduce glycaemic variability (p=0.08). No longterm adverse events were observed. CONCLUSIONS/INTERPRETATION: A 6 day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00627146 FUNDING: Center grants from the Juvenile Diabetes Research Foundation (4-2001-434, 4-2005-1327) and grants from the Belgian Fund for Scientific Research-Flanders and from Brussels Free University-VUB.

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients.

AIMS/HYPOTHESIS: The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A(+) FDRs) of type 1 diabetic patients. METHODS: Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A(+) FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5-10 min) and second (120-150 min) release phase, and after glucagon injection (150-160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT. RESULTS: Seven (41%) FDRs developed diabetes 3-63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p < 0.05) and HVs (p < 0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3-21 months later. Two of seven FDRs with normal first-phase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp. CONCLUSIONS/INTERPRETATION: Clamp-derived functional variables stratify risk of diabetes in IA-2A(+) FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage. TRIAL REGISTRATION: ClinicalTrials.gov NCT00654121 FUNDING: The insulin trial was financially supported by Novo Nordisk Pharma nv.

Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review.

Type 1 diabetes mellitus (T1DM) results from autoimmune destruction of insulin-producing beta cells and is characterised by the presence of insulitis and &and beta-cell autoantibodies. Up to one third of patients develop an autoimmune polyglandular syndrome. Fifteen to 30% of T1DM subjects have autoimmune thyroid disease (Hashimoto's or Graves' disease), 5 to 10% are diagnosed with autoimmune gastritis and/or pernicious anaemia (AIG /PA), 4 to 9% present with coeliac disease (CD), 0.5% have Addison's disease (AD), and 2 to 10% show vitiligo. These diseases are characterised by the presence of autoantibodies against thyroid peroxidase (for Hashimoto's thyroiditis), TSH receptor (for Graves' disease), parietal cell or intrinsic factor (for AIG /PA), tissue transglutaminase (for CD), and 21-hydroxylase (for AD). Early detection of antibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown disease. Hashimoto's hypothyroidism may cause weight gain, hyperlipidaemia, goitre, and may affect diabetes control, menses, and pregnancy outcome. In contrast, Graves' hyperthyroidism may induce weight loss, atrial fibrillation, heat intolerance, and ophthalmopathy. Autoimmune gastritis may manifest via iron deficiency or vitamin B12 deficiency anaemia with fatigue and painful neuropathy. Clinical features of coeliac disease include abdominal discomfort, growth abnormalities, infertility, low bone mineralisation, and iron deficiency anaemia. Adrenal insufficiency may cause vomiting, anorexia, hypoglycaemia, malaise, fatigue, muscular weakness, hyperkalaemia, hypotension, and generalised hyperpigmentation. Here we will review prevalence, pathogenetic factors, clinical features, and suggestions for screening, follow-up and treatment of patients with T1DM and/or autoimmune polyglandular syndrome.

[Improved glucose control and weight loss with exenatide in patients with type 2 diabetes: results of a retrospective observational multicentre Belgian study]. / Amélioration du contrôle glycémique et perte de poids sous exénatide chez des patients diabétiques de type 2: résultats d'une étude rétrospective observationnelle multicentrique belge.

This is a retrospective analysis of medical records in 4 Belgian diabetes centres of 3 cohorts of patients with type 2 diabetes, with data available, respectively, after 3 months < or =163 patients exposed), 6 months (n=77) and 9 months (n=28) with exenatide therapy. This analysis mainly focuses on the 3 and 6 month cohorts. The mean HbA1 level at baseline averaged 9% and decreased by -1.3% and -1.4% at 3 and 6 months, respectively (-1.5% at 9 months). Neither the duration of diabetes nor initial body weight did influence the metabolic response. The decrease in HbA(1c) at 6 months was greater in patients with higher baseline HbA(1c):-0.5%, -1.4% and -2.4% for a baseline HbA(1c) level <8%, 8-10% and >10%, respectively. At 6 months, the composite criterion of a reduction of HbA(1c) by >1% or a final level <7% was reached by 69% of the cohort. Body weight decreased continuously over time, with a mean reduction of -2.1 kg at 3 months and -3.0 kg at 6 months (-4.9 kg at 9 months). The greater the baseline body weight, the greater the weight loss at final evaluation. Minor nausea and more rarely vomiting were observed, essentially during the first months of exenatide treatment. According to this observational study in routine practice, exenatide may be a valuable alternative to insulin for intensification of treatment of patients with type 2 diabetes after failure of oral drug combination, independently of baseline HbA(1c), body weight and duration of diabetes.

Insulin treatment in IA-2A-positive relatives of type 1 diabetic patients.

AIMS: We examined whether parenteral regular insulin can prevent diabetes in IA-2 antibody-positive (IA-2A+) relatives of type 1 diabetic patients, using a trial protocol that differed substantially from that of the Diabetes Prevention Trial-1. METHODS: Twenty-five IA-2A+ relatives received regular human insulin twice a day for 36 months, during which time they were followed (median [interquartile range; IQR]: 47 [19-66] months) for glucose tolerance, HbA(1c) and islet autoantibodies, together with 25 IA-2A+ relatives (observation/control group) who fulfilled the same inclusion criteria, but were observed for 52 [27-67] months (P=0.58). RESULTS: Twelve (48%) insulin-treated relatives and 15 (60%) relatives in the control group developed diabetes. There was no difference in diabetes-free survival between the two groups (P=0.97). Five-year progression (95% confidence interval) was 44% (25-69) in the insulin-treated group and 49% (29-70) in the observation group. At inclusion, progressors tended to have a higher pro-insulin/C-peptide ratio than non-progressors when measured 2 hours after a standardized glucose load (median [IQR]: 2.7% [1.8-4.3] vs. 1.6% [1.1-2.1]; P=0.01). No major hypoglycaemic episodes or significant increases in body mass index or diabetes autoantibodies were observed. CONCLUSION: Prophylactic injections of regular human insulin were well tolerated, but failed to prevent type 1 diabetes onset in IA-2A+ relatives.

The age at diagnosis of type 1 diabetes continues to decrease in Belgian boys but not in girls: a 15-year survey.

BACKGROUND: The age at clinical onset of type 1 diabetes is decreasing. Preliminary Belgian data suggested that this anticipation occurred preferentially in boys. We investigated whether this gender-specific anticipation could be confirmed over a 15-year observation period. METHODS: In Antwerp, we studied incidence trends between 1989 and 2003 in 746 type 1 diabetic patients under age 40. For 2928 antibody-positive patients diagnosed nationwide during the same period, age at diagnosis was analysed according to gender and calendar year. RESULTS: In Antwerp, the incidence of type 1 diabetes under age 15 increased significantly with time from 10.9/100 000/year in 1989-1993 to 15.8/100 000/year in 1999-2003 (p = 0.008). The rising incidence in children was largely restricted to boys under age 10 where the incidence more than doubled during the 15-year period (6.8/100 000/year in 1989-1993 vs 17.2/100 000/year in 1999-2003; p < 0.001). Such an increase was not found in girls under age 10 (p = 0.54). This selective trend toward younger age at diagnosis in boys was confirmed in the larger group of Belgian patients where the median age at diagnosis decreased in boys-but not in girls-from 20 years in 1989-1993 to 15 years in 1999-2003 (p < 0.001). CONCLUSIONS: Over a 15-year observation period, a selective anticipation of clinical onset of type 1 diabetes was found in boys but not in girls. This suggests that an environmental factor may preferentially accelerate the sub-clinical disease process in young boys.

Atypical systemic lupus erythematosus or Castleman's disease.

Collagen vascular diseases and malignancies have common systemic and immune features. We report a case of a 21 year old female patient with constitutional symptoms, polyserositis, spontaneous rupture of the spleen, leukocytoclastic vasculitis and acute renal failure. The tentative diagnosis of SLE was made because she developed a positive antinuclear factor (1/640), with anti-SSA antibodies and a positive lupus anticoagulans. Two months later a cervical lymphadenopathy occurred while recieving treatment with prednisolone. A lymph node biopsy revealed morphologic features of a SLE, similar to those observed in multicentric Castleman's disease (MCD). MCD is a distinct type of a lymphoproliferative disorder of unknown etiology. The difficulties in differential diagnosis of these two diseases are discussed.

Seasonality in clinical onset of type 1 diabetes in belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence.

AIMS/HYPOTHESIS: Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes. METHODS: The seasonal pattern at clinical diagnosis was assessed in 2176 islet antibody-positive diabetic patients aged 0 to 39 years diagnosed between 1989 and 2000. Additional stratification was performed for age, sex and HLA-DQ genotype. RESULTS: Overall, a significant seasonal pattern at clinical diagnosis of diabetes was observed (p<0.001). More subjects were diagnosed in the period of November to February (n=829) than during the period of June to September (n=619) characterised by higher averages of maximal daily temperature and daily hours of sunshine. However, the seasonal pattern was restricted to patients diagnosed above the age of 10 (0-9 years: p=0.398; 10-19 years: p<0.001; 20-29 years: p=0.003; 30-39 years: p=0.015). Since older age at diagnosis is associated with a male to female excess and a lower prevalence of the genetic accelerator HLA-DQ2/DQ8, we further stratified the patients aged 10 to 39 years (n=1675) according to HLA-DQ genotype and sex, and we found that the seasonal pattern was largely restricted to male subjects lacking DQ2/DQ8 (n=748; p<0.00 vs all others: n=927; p=0.031). CONCLUSIONS/INTERPRETATION: In a subgroup of male patients diagnosed over the age of 10, the later stages of the subclinical disease process may be more driven by sex- and season-dependent external factors than in younger, female and genetically more susceptible subjects. These factors may explain the male to female excess in diabetes diagnosed in early adulthood.

A novel 7301-bp deletion in mitochondrial DNA in a patient with Kearns-Sayre syndrome, diabetes mellitus, and primary amenorrhoea.

We report a 27-year-old woman with a form of mitochondrial myopathy including chronic progressive external opthalmoplegia, retinal pigmentary dystrophy, cerebellar ataxia, and cardiac conduction block (Kearns-Sayre syndrome). At age 13 years a cardiac pacemaker was implanted. She also had sensineural hearing loss, delayed puberty, and primary amenorrhoea. She was weelchair-bound since the age of 20 years. At age 27, insulin-dependent diabetes mellitus and osteoporosis were diagnosed. Insulin treatment was started and associated endocrinopathies were investigated. DNA analysis identified a novel 7301-bp deletion in mitochondrial DNA, ranging from position 6530 to 13 831 corroborating the diagnosis of Kearns-Sayre syndrome.

Helicobacter pylori, parietal cell antibodies and autoimmune gastropathy in type 1 diabetes mellitus.

BACKGROUND: Fifteen to 20% of type 1 diabetic patients exhibit parietal cell antibodies (PCA), which are associated with autoimmune gastritis, hypochlorhydria, iron deficiency and pernicious anaemia. AIM: To examine whether Helicobacter pylori infection could explain the high prevalence of PCA and autoimmune gastropathy in diabetes. If so, H. pylori eradication could prevent autoimmune gastritis. METHODS: In 229 type 1 diabetics (M/F: 135/94; age: 41 +/- 12 years) PCA were measured. H. pylori infection was assessed by serology, urea breath test in all and by histology (updated Sydney system) in 88 subjects. Pentagastrin tests were performed in 42 patients. RESULTS: Sixty-nine patients were PCA-positive. H. pylori infection was present in 72 patients and was negatively associated with HLA-DQA1*0103-B1*0603 (OR=0.12, P=0.015) and positively with DQA1*0501-B1*0201 (OR=1.9, P=0.032). PCA-positivity was linked to HLA-DQA1*0501-B1*0301 (OR=3.9, P=0.017). A link between H. pylori and PCA was observed when PCA-positivity was defined as a titre > or = 1/20 (OR=2.0, P=0.03), but not if > or =1/40 was the cut-off point. PCA-positivity, but not H. pylori infection, was associated with iron deficiency anaemia (OR=2.7, P=0.008), pernicious anaemia (OR= 33.5, P < 0.0001), hypochlorhydria (OR=12.1, P=0.0008) and autoimmune gastritis (OR=12.5, P < 0.0001). CONCLUSIONS: The HLA-bound susceptibility of H. pylori and PCA differed. PCA-positivity but not ongoing H. pylori infection is associated with autoimmune gastritis. Low titres of PCA might reflect H. pylori infection rather than autoimmune gastropathy.

Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes.

The autoimmune attack in type 1 diabetes is not only targeted to beta cells. We assessed the prevalence of thyroid peroxidase (aTPO), parietal cell (PCA), antiadrenal (AAA) and endomysial antibodies (EmA-IgA), and of overt autoimmune disease in type 1 diabetes, in relation to gender, age, duration of disease, age at onset, beta-cell antibody status (ICA, GADA, IA2A) and HLA-DQ type. Sera from 399 type 1 diabetic patients (M/F: 188/211; mean age: 26 +/- 16 years; duration: 9 +/- 8 years) were tested for ICA, PCA, AAA and EmA-IgA by indirect immunofluorescence, and for IA2A (tyrosine phosphatase antibodies), GADA (glutamic acid decarboxylase-65 antibodies) and aTPO by radiobinding assays. The prevalence rates were: GADA 70%; IA2A, 44%; ICA, 39%; aTPO, 22%; PCA, 18%; EmA-IgA, 2%; and AAA, 1%. aTPO status was determined by female gender (beta = - 1.15, P = 0.002), age (beta = 0.02, P = 0.01) and GADA + (beta = 1.06, P = 0.02), but not by HLA-DQ type or IA2A status. Dysthyroidism (P < 0.0001) was more frequent in aTPO + subjects. PCA status was determined by age (beta = 0.03, P = 0.002). We also observed an association between PCA + and GADA + (OR = 1.9, P = 0.049), aTPO + (OR = 1.9, P = 0.04) and HLA DQA1*0501-DQB1*0301 status (OR = 2.4, P = 0.045). Iron deficiency anaemia (OR = 3.0, P = 0.003) and pernicious anaemia (OR = 40, P < 0.0001) were more frequent in PCA + subjects. EmA-IgA + was linked to HLA DQA1*0501-DQB1*0201 + (OR = 7.5, P = 0.039), and coeliac disease was found in three patients. No patient had Addison's disease. In conclusion, GADA but not IA2A indicate the presence of thyrogastric autoimmunity in type 1 diabetes. aTPO have a female preponderance, PCA are weakly associated with HLA DQA1*0501-DQB1*0301 and EmA-IgA + with HLA DQA1*0501-DQB1*0201.

The presence of thyrogastric antibodies in first degree relatives of type 1 diabetic patients is associated with age and proband antibody status.

A quarter of type 1 diabetic patients have thyrogastric autoantibodies (thyroid peroxidase and gastric parietal cell antibodies). Clinical, immune, and genetic risk factors help predict antibody status. First degree relatives of these patients may also frequently exhibit these antibodies. We assessed the prevalence of thyrogastric antibodies and dysfunction in first degree relatives in relation to age, gender, human leukocyte antigen-DQ type, beta-cell antibody (islet cell, glutamic acid decarboxylase-65, and tyrosine phosphatase antibodies), and proband thyrogastric antibody status. Sera from 272 type 1 diabetic patients (116 men and 156 women; mean age, 27 +/- 18 yr; duration, 10 +/- 9 y), 397 first degree relatives (192 men and 205 women; parents/siblings/offspring, 48/222/127; age, 22 +/- 10 yr), and 100 healthy controls were tested for islet cell antibodies and gastric parietal cell antibodies by indirect immunofluorescence and for tyrosine phosphatase, glutamic acid decarboxylase-65, and thyroid peroxidase antibodies by radiobinding assays. Glutamic acid decarboxylase-65 antibodies were present in 68% and 5%, islet cell antibodies were present in 36% and 2.5%, tyrosine phosphatase antibodies were present in 45% and 0.5%, thyroid peroxidase antibodies were present in 21% and 4.5%, and gastric parietal cell antibodies were present in 18% and 11% of diabetic patients and relatives, respectively. The presence of thyroid peroxidase antibodies in relatives was determined by age (beta = 0.22; P = 0.0001) and proband thyroid peroxidase antibodies status (beta = -2.6; P = 0.002; odds ratio = 11.1). Gastric parietal cell antibody positivity in relatives was associated with age (beta = 0.04; P = 0.026). Gastric parietal cell antibody-positive compared with gastric parietal cell antibody-negative relatives were more likely to have gastric parietal cell antibody-positive probands (P = 0.01; odds ratio = 3.0). beta-Cell antibody status and human leukocyte antigen-DQ type did not influence thyrogastric antibody status in relatives. (Sub)clinical dysthyroidism was found in 3%, iron deficiency anemia was present in 12% (26% gastric parietal cell antibody-positive and 9% gastric parietal cell antibody-negative subjects; P = 0.009), and pernicious anemia was found in 0.5% (5% gastric parietal cell antibody-positive and 0% gastric parietal cell antibody-negative subjects; P = 0.012) of relatives. They had less thyroid dysfunction (P < 0.0001) and pernicious anemia (P = 0.018) than diabetic probands. In conclusion, thyrogastric antibodies and dysfunction are more prevalent in type 1 diabetic patients than in first degree relatives. The presence of these antibodies in relatives is associated with age and proband antibody status, but not with beta-cell antibodies or human leukocyte antigen-DQ type.

Low-density lipoprotein receptor gene mutation analysis and clinical correlation in Belgian hypercholesterolaemics.

It is generally believed that patients with familial hypercholesterolaemia (FH) have a higher cardiovascular risk than hypercholesterolaemics without a defect in the low-density lipoprotein receptor (LDLR) gene. However, no conclusive evidence to support this view has yet been presented. We investigated this aspect in Belgian hyperlipidaemics as part of a comprehensive effort to determine the impact of FH in this population. DNA samples of 98 unrelated Belgian patients with a family history of autosomal dominant hypercholesterolaemia were screened for mutations in the LDLR gene, after exclusion of known mutations causing familial defective apolipoprotein B-100 (FDB). Eight of the 22 distinct LDLR gene mutations identified in 27 subjects have not previously been described in other populations. As expected, the mutation-positive patients had a significantly worse lipid profile than the mutation-negative subjects (p<0.05), but this did not correlate with clinical cardiovascular status. In conclusion, the presence of a mutation in the LDLR gene was not a reliable predictor of cardiovascular risk in the hyperlipidaemic subjects included in this study. However, it is possible that prolonged exposure to the high levels of LDL cholesterol in genetically proven FH patients will in future cause a higher incidence of coronary heart disease. Our data may reflect the genetic heterogeneity of inherited hypercholesterolaemia, recently shown to be caused by several major genes.

Gastric parietal cell antibodies are associated with glutamic acid decarboxylase-65 antibodies and the HLA DQA1*0501-DQB1*0301 haplotype in Type 1 diabetes mellitus. Belgian Diabetes Registry.

AIMS: To assess the prevalence of thyrogastric autoimmunity in relation to age, sex, beta-cell antibody status and HLA DQ haplotypes in Type 1 diabetes mellitus. METHODS: One hundred and seventy-one patients with Type 1 diabetes mellitus were studied (male/female 86/85; mean age 19 +/- 11 years; duration of diabetes 5 +/- 4 years). Islet cell antibodies (ICA) and parietal cell antibodies (PCA) were measured using indirect immunofluorescence; glutamic acid decarboxylase-65 antibodies (GADA) by radiobinding assay and thyroid peroxidase antibodies (TPO) with an immunoradiometric assay (IRMA). RESULTS: The majority of subjects (81.3%) showed one or more autoantibodies. The prevalence rates were: GADA 64.9%, ICA 46.2%, PCA 19.9% and TPO 19.3%. Patients with ICA+ > or = 3 years after diagnosis had a higher prevalence of GADA (P = 0.03, odds ratio (OR) 2.66) and thyrogastric antibodies (P = 0.05, OR 2.23) than subjects ICA- after 3 years. PCA+ patients were older (P = 0.04), had a higher prevalence of GADA (P = 0.005, OR 3.89) and TPO (P = 0.05, OR 2.50) than PCA- subjects. Logistic regression analysis showed that PCA status was determined by the HLA DQA1*0501-DQB1*0301 haplotype (beta = 2.94, P = 0.04) and GADA status (beta = 2.44, P = 0.041). CONCLUSIONS: Thyrogastric antibodies are highly prevalent in Type 1 diabetes mellitus, especially in patients with persisting ICA. Screening for gastric autoimmunity is particularly advised in patients who are positive for GADA and for the HLA DQA1*0501-DQB1*0301 haplotype.