Selective IgA Deficiency and Allergy: A Fresh Look to an Old Story

Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.

Vitamin D Deficiency Is Associated with Glycometabolic Changes in Nondiabetic Patients with Arterial Hypertension

Recent evidence indicates that mildly increased fasting and post-oral load blood glucose concentrations contribute to development of organ damage in nondiabetic patients with hypertension. In previous studies, vitamin D deficiency was associated with decreased glucose tolerance. The aim of this study was to examine the relationships between serum 25(OH)D levels and glucose tolerance and insulin sensitivity in hypertension. In 187 nondiabetic essential hypertensive patients free of cardiovascular or renal complications, we measured serum 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) and performed a standard oral glucose tolerance test (OGTT). Patients with 25(OH)D deficiency/insufficiency were older and had significantly higher blood pressure, fasting and post-OGTT (G-AUC) glucose levels, post-OGTT insulin (I-AUC), PTH levels, and prevalence of metabolic syndrome than patients with normal serum 25(OH)D. 25(OH)D levels were inversely correlated with age, blood pressure, fasting glucose, G-AUC, triglycerides, and serum calcium and PTH, while no significant relationships were found with body mass index (BMI), fasting insulin, I-AUC, HOMA index, and renal function. In a multivariate regression model, greater G-AUC was associated with lower 25(OH)D levels independently of BMI and seasonal vitamin D variations. Thus, in nondiabetic hypertensive patients, 25(OH)D deficiency/insufficiency could contribute to impaired glucose tolerance without directly affecting insulin sensitivity.

An Interesting Case of Nonlupus Full-House Nephropathy

Full-house immunofluorescence and endothelial tubuloreticular inclusions are known as characteristic features of lupus nephritis. However, both features are not pathognomonic for lupus nephritis. A kidney biopsy specimen showing full-house immunofluorescence pattern in the absence of autoantibodies and classical clinical features of Systemic Lupus Erythematosus (SLE) is now considered as nonlupus full-house nephropathy (FHN). Nonlupus FHN may be idiopathic or due to other disease processes known as secondary nonlupus FHN. Here, we report the case of a 36-year-old female who presented with nephrotic proteinuria with bland urine sediment. Additional analyses revealed normal serum antinuclear antibody (ANA), normal anti-double-stranded DNA (anti-dsDNA) antibodies, and normal serum C3 and C4 levels. A renal biopsy showed a normal-appearing glomerulus without any proliferation or capillary wall thickening and widespread glomerular immune deposits (full-house effect; IgA, IgG, IgM, C3, and C1Q) on direct immunofluorescence. Renal electron microscopy showed diffuse effacement of visceral epithelial cell foot processes and mesangial electron dense deposits. The patient was diagnosed as nonlupus FHN. There is a controversial role of steroids and other immunosuppressive drugs in the treatment of nonlupus FHN patients, but our case patient responded favourably to steroid therapy. The term nonlupus FHN can be used as an umbrella term for patients who do not satisfy the clinical and serological criteria of SLE.

Mauriac Syndrome in a Nigerian child with Type 1 Diabetes Mellitus: A Case Report

A 14-year-old boy with Type 1 Diabetes mellitus (diagnosed at eight years of age) presented with complaints of fever, weight loss, growth failure, pubertal delay, abdominal swelling and discomfort. He was on Premixed insulin (70/30) with inadequate follow-up and poor diabetic control. Examination revealed cachexia, generalised lymphadenopathy, a protuberant abdomen and hepatosplenomegaly. Anthropometry showed a bodyweight of 19.6kg, a height of 116cm and a BMI of 14.1kg/m2, all markedly below the 3rd centile. He had no secondary sexual characteristics: axillary hair stage 1, pubic hair stage 1, penile length of 4.9cm and prepubertal testicular volumes of 3mls bilaterally. At presentation, his random blood glucose was 400mg/dl, and glycosylated haemoglobin was 11.6%. Screening for tuberculosis, human immunodeficiency virus, hepatitis and lymphoproliferative disorders were negative. Other blood investigation findings included leucocytosis, erythrocyte sedimentation rate of 30mm/hr, normal liver function tests, normal serum electrolytes, urea and creatinine. His haemoglobin genotype was AS. Chest radiograph showed features of bronchopneumonia. A presumptive diagnosis of Mauriac Syndrome was made. With the optimisation of glycaemic control, he improved clinically with a weight gain of 5.7kg over four months and resolution of hepatosplenomegaly.

The Effectiveness and Safety of Calcium Carbonate Use in Chronic Kidney Disease Patients with Normophosphatemia

Background: Patients with early and moderate stages of chronic kidney disease (CKD) have normal serum phosphate levels. Increased fibroblast growth factor-23 (FGF23) levels in these patients are responsible for maintaining normophosphatemia status by increasing the excretion of phosphate through urine. However, an increased serum FGF23 level is related to cardiomegaly, vascular calcification, CKD progression, and mortality. This study aimed to examine the effectiveness and safety of calcium carbonate use in stage 3 or 4 CKD patients with normophosphatemia. Methods: This double-blind randomized controlled trial (ClinicalTrials.gov identifier NCT03550534) included stage 3 or 4 CKD patients with normophosphatemia who visited the nephrology or endocrinology clinic at Dr. Cipto Mangunkusumo Hospital. Forty-six subjects were randomized to receive either calcium carbonate or placebo over a 12-weeks period. Urine phosphate, serum phosphate, serum calcium, and serum intact FGF23 levels were measured before and after the intervention. Results: The baseline characteristics of the two groups were similar, except for the higher prevalence of dyslipidemia in the placebo group. The CaCO3 group had shown reduced levels of FGF23 compared to the placebo group, -8.03 vs. 0.15 pg/ml respectively (p = 0.019). The median level of FGF23 showed a significant decrease only in the CaCO3 group. An increase in eGFR and a slightly decrease in urine phosphate were observed in the CaCO3 group; however, the data was found to be statistically not significant. No significant changes were noted in the serum calcium levels in both groups. Conclusion: The administration of calcium carbonate has been shown to be effective and safe for moderate CKD patients with normophosphatemia due to its effect in lowering FGF23 levels without escalating the serum calcium level.

ALPL genotypes in patients with atypical femur fractures or other biochemical and clinical signs of hypophosphatasia

Context Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue non-specific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the administration of contraindicated antiresorptive drugs that, in HPP patients, substantially increase the risk of atypical femur fractures (AFFs) and worsen fracture healing process that is usually already compromised in these patients. Objective Performing ALPL genetic testing to identify rare variants in suspected adult HPP patients. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP. Design Patients with suspected adult HPP were retrospectively selected for the genetic testing of the ALPL gene. Setting Patients included were from three main European Bone Units (Florence, Naples and Geneva). Patients 106 patients with biochemical and/or clinical signs suggestive of a mild form of HPP. Results and conclusions Genetic testing led to the identification of a heterozygote rare variant in 2.8% of cases, who were initially referred as suspected osteoporosis. The analysis of frequencies of ALPL common variants showed a high prevalence (30.8%) of homozygosity in subjects who developed an AFF, in association with normal serum total ALP activity, suggesting this as a possible genetic marker of risk for these fractures.

Setting for “Normal” Serum Ferritin Levels in Patients with Transfusion-Dependent Thalassemia: Our Current Strategy

This cross-sectional study aimed to establish the association between serum ferritin levels and organ iron overload (IO) and overall morbidity in transfusion-dependent thalassemia (TDT) patients. One hundred and three TDT patients (40.03 ± 9.15 years; 57.3% females) with serum ferritin < 2500 ng/mL were included. IO was assessed by T2* magnetic resonance imaging. Three groups were identified based on mean serum ferritin levels: <500 ng/mL (group 0; N = 32), 500–1000 ng/mL (group 1; N = 43), and 1000–2500 ng/mL (group 2; N = 28). All demographic and biochemical parameters were comparable among the three groups, with the exception of the triglycerides being significantly lower in group 0 than in group 2. No difference was found in the frequency of hepatic, endocrine, and cardiac complications. Hepatic IO was significantly less frequent in group 0 versus both groups 1 and 2. No patient with a serum ferritin level < 500 ng/mL had significant myocardial IO and alterations in the main hematological parameters. No difference in the distribution of the different chelation regimens was found. Serum ferritin < 500 ng/mL appears to be achievable and safe for several TDT patients. This target is associated with the absence of significant cardiac iron and significantly lower hepatic IO and triglycerides that are well-demonstrated markers for cardiac and liver complications.

Progesterone induced blocking factor in health and disease

The foetus expressing paternal antigens ought to be “rejected” by the maternal immune system. However, the immunological relationship of the mother and the foetus does not follow the rules of transplantation immunology. Maternal immune functions are re-adjusted during pregnancy, to create a tolerant environment for the developing foetus. Progesterone and its downstream mediator; the progesterone induced blocking factor (PIBF) are important in this process. The mRNA transcribed from the PIBF1 gene contains 18 exons, and codes for a 90 kDa protein. The 90 kDa form is associated with the centrosome and plays a role in cell cycle regulation, while smaller isoforms produced by alternative spicing are secreted, and bind to the glycosylphosphatidylinositol (GPI) anchored PIBF receptor. Upon ligation, the former forms a heterodimer with the alpha chain of the interleukin-4 (IL-4) receptor and activates the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, via which, PIBF induces increased production of T helper2 (Th2) cytokines. PIBF regulates natural killer (NK) cytotoxicity, by inhibiting perforin release from the cytoplasmic granules of NK cells. During normal human pregnancy, the serum concentrations of PIBF increase with gestational age, and lower than normal serum levels predict spontaneous pregnancy termination. Depletion of PIBF during the peri-implantation period in mice, results in lower implantation and increased resorption rates, together with increased decidual and peripheral NK activity, downregulation of the genes implicated in T cell activation in CD4+ cells, and Th1 differentiation of the T cells. PIBF is expressed in rapidly proliferating immature cells as well as several tumours, and regulates invasion. The PIBF gene has been identified in the chromosomal region 13q21-q22—which is a common site for somatic deletions in a variety of malignant tumours. These data suggest that PIBF might be involved in tumorigenesis.