Pekka Arikoski

Parenteral plant sterols and intestinal failure-associated liver disease in neonates.

Objectives: We prospectively evaluated incidence of prolonged (>28 days) parenteral nutrition (PN), associated complications, and significance of parenteral plant sterols (PS) in neonatal intestinal failure–associated liver disease (IFALD) compared with children. Methods: We recruited 28 neonates (mean age 50 days, range 28–126) and 11 children (6.9 y, 2.1–16.6) in all of Finland. Patients underwent repeated measurements of serum cholesterol, noncholesterol sterols, including PS, cholestanol and cholesterol precursors, and liver biochemistry during and 1 month after discontinuation of PN. Healthy matched neonates (n = 10) and children (n = 22) served as controls. Results: IFALD occurred more frequently among neonates (63%) than children (27%; P < 0.05). Ratios of serum PS, including stigmasterol, sitosterol, avenasterol, and campesterol, and total PS were increased among neonates compared with healthy controls and children on PN by 2- to 22- and 2- to 5-fold (P < 0.005), respectively. Neonates with IFALD had significantly higher ratios of serum PS and cholestanol compared with neonates without IFALD (P < 0.05). Total duration of PN associated with serum cholestanol, stigmasterol, avenasterol, alanine aminotransferase, and aspartate aminotransferase (r = 0.472–0.636, P < 0.05). Cholestanol and individual serum PS, excluding campesterol, reflected direct bilirubin (r = 0.529–0.688, P < 0.05). IFALD persisted after discontinuation of PN in 25% of neonates with 4.2- and 2.2-times higher ratios of serum stigmasterol and cholestanol compared with neonates without IFALD (P < 0.05). Conclusions: Frequent occurrence of IFALD among neonates on PN displays an association to duration of PN and markedly increased serum PS, especially stigmasterol, in comparison to healthy neonates and children on PN. Striking accumulation of parenteral PS may contribute to IFALD among neonates.

Renal manifestations of Henoch–Schönlein purpura in a 6-month prospective study of 223 children

Objective To assess the risk factors for developing Henoch–Schönlein purpura nephritis (HSN) and to determine the time period when renal involvement is unlikely after the initial disease onset. Design A prospective study of 223 paediatric patients to examine renal manifestations of Henoch–Schönlein purpura (HSP). The patients condition was monitored with five outpatient visits to the research centre and urine dipstick testing at home. Results HSN occurred in 102/223 (46%) patients, consisting of isolated haematuria in 14%, isolated proteinuria in 9%, both haematuria and proteinuria in 56%, nephrotic-range proteinuria in 20% and nephrotic-nephritic syndrome in 1%. The patients who developed HSN were significantly older than those who did not (8.2±3.8 vs 6.2±3.0 years, p<0.001, CI for the difference 1.1 to 2.9). Nephritis occurred a mean of 14 days after HSP diagnosis, and within 1 month in the majority of cases. The risk of developing HSN after 2 months was 2%. Prednisone prophylaxis did not affect the timing of the appearance of nephritis. The risk factors for developing nephritis were age over 8 years at onset (OR 2.7, p=0.002, CI 1.4 to 5.1), abdominal pain (OR 2.1, p=0.017, CI 1.1 to 3.7) and recurrence of HSP disease (OR 3.1, p=0.002, CI 1.5 to 6.3). Patients with two or three risk factors developed nephritis in 63% and 87% of cases, respectively. Laboratory tests or blood pressure measurement at onset did not predict the occurrence of nephritis. Conclusion The authors recommend weekly home urine dipstick analyses for the first 2 months for patients with HSP. Patients with nephritis should be followed up for more than 6 months as well as the patients with HSP recurrence.

Reduced bone density at completion of chemotherapy for a malignancy

OBJECTIVES Osteoporosis and pathological fractures occur occasionally in children with malignancies. This study was performed to determine the degree of osteopenia in children with a malignancy at completion of chemotherapy. METHODS Lumbar spine (L2–L4) bone mineral density (BMD; g/cm2) and femoral neck BMD were measured by dual energyx ray absorptiometry in 22 children with acute lymphoblastic leukaemia (ALL), and in 26 children with other malignancies. Apparent volumetric density was calculated to minimise the effect of bone size on BMD. Results were compared with those of 113 healthy controls and expressed as age and sex standardised mean Z scores. RESULTS Patients with ALL had significantly reduced lumbar volumetric (−0.77) and femoral areal and volumetric BMDs (−1.02 and −0.98, respectively). In patients with other malignancies, femoral areal and apparent volumetric BMDs were significantly decreased (−0.70 and −0.78, respectively). CONCLUSIONS The results demonstrate that children with a malignancy are at risk of developing osteopenia. A follow up of BMD after the completion of chemotherapy should facilitate the identification of patients who might be left with impaired development of peak bone mass, and who require specific interventions to prevent any further decrease in their skeletal mass and to preserve their BMD.

Impaired Development of Bone Mineral Density During Chemotherapy: A Prospective Analysis of 46 Children Newly Diagnosed with Cancer

Osteopenia and osteoporosis are becoming increasingly recognized in children with cancer, though reasons for these changes are poorly understood. The purpose of the present study was to evaluate longitudinal changes in bone mineral density (BMD) and bone turnover in newly diagnosed children with a malignancy. Lumbar spine (L2–L4) and femoral neck bone mineral density (BMDareal, g/cm2) was measured by dual‐energy X‐ray absorptiometry in 46 children (age 2.9–16.0, median 8.0 years; 15 leukemias, 12 lymphomas, 19 solid tumors) at diagnosis, and after 6 months from the baseline. The apparent volumetric bone mineral density (BMDvol) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxy‐terminal propeptide (PICP), and type I collagen carboxy‐terminal telopeptide (ICTP) were analyzed at diagnosis, and during a 6‐month follow‐up. A significant decrease in lumbar BMDvol (–2.1%, p < 0.05), and in femoral BMDareal (–9.9%, p = 0.0001) and BMDvol (–8.5%, p = 0.0001) was observed after 6 months when compared with baseline measurements. The markers of bone formation (PICP, OC) were significantly decreased, and the marker of bone resorption (ICTP) was significantly increased at diagnosis as compared with normal values. By the end the follow‐up, the levels of PICP and OC were normalized, whereas the level of ICTP continued to increase indicating that there was a negative balance in bone turnover. A deficient accumulation of bone mass might predispose children with a malignancy to impaired development of peak bone mass. A controlled study determining the benefits of an early intervention on bone turnover should be considered in these patients.

Clinical course of extrarenal symptoms in Henoch–Schönlein purpura: a 6-month prospective study

Objective To describe the extrarenal symptoms and clinical course of Henoch–Schönlein purpura (HSP). Design A prospective national multicentre trial with 6-month follow-up. Patients A total of 223 newly diagnosed paediatric HSP patients. Results Purpura was the initial symptom in 73% of the patients and was preceded by joint or gastrointestinal manifestations in the rest by a mean of 4 days. Joint symptoms, abdominal pain, melena, nephritis and recurrences occurred in 90%, 57%, 8%, 46% and 25% of the patients, respectively. Orchitis affected 17/122 (14%) of the boys. Seven patients developed protein-losing enteropathy characterised by abdominal pain, oedema and serum albumin under 30 g/l, and an additional 49 patients had subnormal albumin levels without any proteinuria. Positive fecal occult blood (26/117, 22%) and α1-antitrypsin (7/77, 9%) suggested mucosal injury even in the patients without gastrointestinal symptoms. HSP was often preceded by various bacterial, especially streptococcal (36%) and viral infections. Previous streptococcal infection did not induce changes in the level of complement component C3. Recurrences were more frequent in patients >8 years of age (OR 3.7, CI 2.0 to 7.0, p<0.001) and in patients with nephritis (OR 4.6, CI 2.3 to 8.9, p<0.001). Patients with severe HSP nephritis had more extrarenal symptoms up to 6 months. There was no difference in the clinical course between the prednisone-treated and non-treated patients during the 6-month follow-up. Conclusions Serum albumin is often low in HSP patients without proteinuria, due to protein loss via the intestine. Although corticosteroids alleviate the symptoms, they seem not to alter the clinical course of HSP during 6 months of follow-up.

Biochemical Markers of Bone Metabolism in Relation to Adrenocortical and Growth Suppression During the Initiation Phase of Inhaled Steroid Therapy

Growth suppression is usually most evident during the first year of inhaled steroid therapy. Steroid-induced changes in bone metabolism may contribute to this growth suppression. The aim of the present study was to evaluate the changes in biochemical markers of bone metabolism in relation to adrenal and growth suppression during the initiation phase of inhaled steroid therapy. Seventy-five school-aged children with new asthma were enrolled into budesonide (BUD, n = 30), fluticasone propionate (FP, n = 30) or cromone (CROM, n = 15) treatment groups. BUD dose was 800 μg/d during the first two months and 400 μg/d thereafter. The respective FP doses were 500 and 200 μg/d. Biochemical markers of bone metabolism were measured before treatment and after 2 and 4 mo of therapy. In the control (CROM) group, the mean concentrations of serum osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP) (formation markers) and type I collagen carboxyterminal telopeptide (ICTP) (degradation marker) tended to increase. In the BUD group, OC and PICP decreased during the 4 mo by a mean of 23% (p < 0.001) and 15% (p < 0.05), respectively, while ICTP did not change significantly. In the FP group, OC and ICTP decreased during the first 2 mo by a mean of 19% (p < 0.01) and 21% (p < 0.01), respectively, returning to the pretreatment level at 4 mo, while PICP tended to increase during the 4 mo (14%, p = 0.12). In the steroid treated children whose height SD score decreased during the first 12 mo of therapy, both OC and PICP decreased during the first 4 mo by a mean of 20% (p < 0.01) and 21% (p < 0.001), respectively. In those children who had no growth suppression, the changes were not significant: −4% in OC and +13% in PICP. Furthermore, in children who developed evidence of adrenocortical suppression (on the basis of a low-dose ACTH test), OC decreased more (23%, p < 0.01) than in those with normal adrenocortical function (10%, p = 0.06). In conclusion, both inhaled BUD and FP caused dose-dependent effects on biochemical markers of bone metabolism. The children who developed growth or adrenocortical suppression were likely to have changes also in bone metabolism.

Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study.

PURPOSE To evaluate the occurrence and characteristics of uveitis related to tubulointerstitial nephritis (TIN) in children. DESIGN Prospective, observational, multicenter, partly placebo-controlled treatment trial. PARTICIPANTS Nineteen children with a biopsy-proven TIN. METHODS Patients were treated with prednisone or followed without treatment. In addition to the nephrologic evaluations, the prospective follow-up included structured ophthalmological examinations at the onset of TIN and at 3 and 6 months after the diagnosis. MAIN OUTCOME MEASURES Occurrence, clinical features, and outcome of uveitis. RESULTS Some 84% (16/19) of the patients had uveitis, 83% (5/6) in the nontreatment group and 82% (9/11) in the prednisone-treated group. The remaining 2 patients, originally in the nontreatment group, were switched to the prednisone group after 2 weeks. Both of them developed uveitis. Altogether, 3 patients developed uveitis during prednisone treatment and 2 patients showed worsening of uveitis despite the systemic corticosteroid. Some 50% (8/16) of the patients with uveitis presented with no ocular symptoms; 88% (14/16) of the patients had a chronic course of uveitis. Two patients were diagnosed with uveitis before nephritis; nephritis and uveitis were diagnosed within 1 week from each other in 7 patients, and uveitis developed 1 to 6 months after the diagnosis of TIN in 7 patients. CONCLUSIONS There was no statistically significant difference in the occurrence of uveitis in patients with TIN in the prednisone and nontreatment groups. In this study, the occurrence of uveitis associated with TIN was considerably higher than previously reported. Uveitis related to TIN may develop late and is often asymptomatic. The ophthalmological follow-up of all patients with TIN is warranted for at least 12 months starting with 3-month intervals. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any material discussed in this article.

Novel NPHS2 variant in patients with familial steroid-resistant nephrotic syndrome with early onset, slow progression and dominant inheritance pattern

BackgroundSteroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS.MethodsWe analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease. We carried out a whole genome sequencing in two affected and two healthy family members. The function of found podocin variant was studied using co-immunoprecipitation and immunohistochemistry. Podocyte gene sequences were analyzed in a cohort of Finnish non-familial SRNS patients.ResultsA heterozygous de novo deletion, c.988_989delCT in NPHS2, was found in all affected family members and in none of their healthy relatives, non-familial patients or controls. No other SRNS-related gene variant, coding or non-coding co-segregated with the disease phenotype in the family. While the truncated podocin remained able to bind nephrin, the expression of nephrin was fragmented and podocin expression reduced. The gene analysis of the non-familial SRNS patients revealed few variants.ConclusionThe role of podocin variants in nephrotic syndrome may be more varied than previously thought.

Development of gliadin-specific immune responses in children with HLA-associated genetic risk for celiac disease

Abstract Objective. The development of gliadin-specific antibody and T-cell responses were longitudinally monitored in young children with genetic risk for celiac disease (CD). Material and methods. 291 newborn children positive for HLA-DQB1*02 and -DQA1*05 alleles were followed until 3–4 years of age by screening for tissue transglutaminase autoantibodies (tTGA) by using a commercial ELISA-based kit and antibodies to deamidated gliadin peptide (anti-DGP) by an immunofluorometric assay. Eighty-five of the children were also followed for peripheral blood gliadin-specific CD4+ T-cell responses by using a carboxyfluorescein diacetate succinimidyl ester-based in vitro proliferation assay. Results. The cumulative incidence of tTGA seropositivity during the follow-up was 6.5%. CD was diagnosed in nine of the tTGA-positive children (3.1%) by duodenal biopsy at a median 3.5 years of age. All of the children with confirmed CD were both IgA and IgG anti-DGP positive at the time of tTGA seroconversion and in over half of the cases IgG anti-DGP positivity even preceded tTGA seroconversion. Peripheral blood T-cell responses to deamidated and native gliadin were detected in 40.5% and 22.2% of the children at the age of 9 months and these frequencies decreased during the follow-up to the levels of 22.2% and 8.9%, respectively. Conclusions. Anti-DGP antibodies may precede tTGA seroconversion and thus frequent monitoring of both tTGA and anti-DGP antibodies may allow earlier detection of CD in genetically susceptible children. Peripheral blood gliadin-specific T-cell responses are relatively common in HLA-DQ2-positive children and are not directly associated with the development of CD.

Early fecal microbiota composition in children who later develop celiac disease and associated autoimmunity

Abstract Objectives: Several studies have reported that the intestinal microbiota composition of celiac disease (CD) patients differs from healthy individuals. The possible role of gut microbiota in the pathogenesis of the disease is, however, not known. Here, we aimed to assess the possible differences in early fecal microbiota composition between children that later developed CD and healthy controls matched for age, sex and HLA risk genotype. Materials and methods: We used 16S rRNA gene sequencing to examine the fecal microbiota of 27 children with high genetic risk of developing CD. Nine of these children developed the disease by the age of 4 years. Stool samples were collected at the age of 9 and 12 months, before any of the children had developed CD. The fecal microbiota composition of children who later developed the disease was compared with the microbiota of the children who did not have CD or associated autoantibodies at the age of 4 years. Delivery mode, early nutrition, and use of antibiotics were taken into account in the analyses. Results: No statistically significant differences in the fecal microbiota composition were found between children who later developed CD (n = 9) and the control children without disease or associated autoantibodies (n = 18). Conclusions: Based on our results, the fecal microbiota composition at the age of 9 and 12 months is not associated with the development of CD. Our results, however, do not exclude the possibility of duodenal microbiota changes or a later microbiota-related trigger for the disease.