Association between low C-peptide and fragility fractures in postmenopausal women without diabetes.

PURPOSE: C-peptide has been shown to exert several, previously unknown, biological effects. A recent cross-sectional study demonstrated an association between low C-peptide serum levels and low lumbar bone density of postmenopausal women not affected by diabetes. To date, very little research attention has been directed toward the association between C-peptide and osteoporotic fractures. To contribute toward filling this gap, we investigated the association between C-peptide and fractures in postmenopausal women. METHODS: A cohort of 133 non-diabetic postmenopausal women with and without a history of fractures was evaluated in this cross-sectional investigation. Standardized interviews were performed to gather information on the patients' fracture history. All of the participants underwent a bone mineral density assessment by DXA, radiographs, and a serum C-peptide measurement. RESULTS: Thirty-four women presented fractures. Bivariate analysis revealed an inverse correlation between C-peptide and fractures (r = -0.27, p = 0.002). A significant difference in mean C-peptide levels was also found between women with vs. without fractures (p = 0.01, adjusted for age, BMI and glucose). Logistic regression analysis showed that C-peptide levels, femoral and vertebral BMD were all negatively associated with fracture status (B = -1.097, ES = 0.401, p = 0.006, 95% CI 0.15-0.73; B = -15.6, SE = 4.17, p < 0.001, CI 0.001-0.002; B = -24.8, SE = 5.23, p < 0.001, CI 0001-0.002; respectively). CONCLUSIONS: This study confirms an inverse association between serum C-peptide levels and a history of fractures in postmenopausal women without diabetes. These results suggest that C-peptidemay exert an effect on bone mineral density. However, further large-scale studies are needed to corroborate this finding and investigate the potential underlying mechanisms involved.

Wnt signaling pathway inhibitors as promising diagnostic serum markers of osteolytic bone metastasis.

Despite the clinical importance of bone metastases, we still know little about their onset and progression and current diagnostic tools lack the sensitivity and specificity required for clear early diagnosis. We therefore need to continue studying the pathogenesis of bone metastatic invasion in order to improve diagnosis. The Wnt pathway has been described as having an important role in bone carcinogenesis and metastatic progression. This study investigated the diagnostic potential of the two main Wnt inhibitors, sclerostin and DKK-1, to improve the detection of osteolytic bone metastases. We measured sclerostin and DKK-1, MMP-2 and MMP-9, the bone resorption marker TRAP5b and the metastatic marker survivin in a control group of healthy patients, in patients with primary tumors and in a group with metastasis. Sclerostin and DKK-1 were clearly high in primary tumor patients and even higher in metastatic patients, compared to controls. The close correlations with metastatic markers and bone resorption markers make sclerostin and DKK-1 promising as new biomarkers in the diagnosis of bone osteolytic metastases.

Epicardial adipocyte hypertrophy: Association with M1-polarization and toll-like receptor pathways in coronary artery disease patients.

BACKGROUND AND AIMS: In coronary artery disease (CAD) epicardial adipose tissue (EAT) shows an elevated inflammatory infiltrate. Toll-like receptors (TLRs) are important mediators of adipose tissue inflammation and they are able to recognize endogenous products released by damaged cells. Because adipocyte death may be driven by hypertrophy, our aim was to investigate in CAD and non-CAD patients the association between EAT adipocyte size, macrophage infiltration/polarization and TLR-2 and TLR-4 expression. METHODS AND RESULTS: EAT biopsies were collected from CAD and non-CAD patients. The adipocyte size was determined by morphometric analysis. Microarray technology was used for gene expression analysis; macrophage phenotype and TLRs expression were analyzed by immunofluorescence and immunohistochemical techniques. Inflammatory mediator levels were determined by immunoassays. EAT adipocytes were larger in CAD than non-CAD patients and do not express perilipin A, a marker of lipid droplet integrity. In CAD, EAT is more infiltrated by CD68-positive cells which are polarized toward an M1 state (CD11c positive) and presents an increased pro-inflammatory profile. Both TLR-2 and TLR-4 expression is higher in EAT from CAD and observed on all the CD68-positive cells. CONCLUSIONS: Our findings suggested that EAT hypertrophy in CAD promotes adipocyte degeneration and drives local inflammation through increased infiltration of macrophages which are mainly polarized towards an M1 state and express both TLR-2 and TLR-4.

Circulating sRAGE in the diagnosis of osteolytic bone metastasis.

Despite the clinical importance of metastasis to the skeleton, the diagnostic tools for early detection and monitoring of bone metastasis lack sensitivity and specificity. We evaluated a promising new serum biomarker, the soluble form of the Receptor of Advanced Glycosylated End-products (sRAGE). sRAGE is involved in the Wnt-signaling pathway, and has been reported to reduce the risk of cancer. We investigated the diagnostic potential of sRAGE to improve the detection and monitoring of bone metastasis. We measured sRAGE in the serum of control healthy subjects, patients with primary tumors and patients with bone metastasis. sRAGE was also correlated with the Wnt inhibitors DKK-1 and sclerostin, the bone resorption markers MMP-2, MMP-9 and TRAP5, and the metastatic marker survivin. sRAGE was significantly lower in primary tumor and metastatic patients than in healthy subjects. sRAGE also showed a strong negative correlation with DKK-1, sclerostin, MMP-2, MMP-9, TRAP5b and survivin. These results indicated that sRAGE might play a protective role in bone metastasis progression, and it may diagnostic significance for detecting and monitoring osteolytic metastases.

Association between low C-peptide and low lumbar bone mineral density in postmenopausal women without diabetes.

UNLABELLED: In this population-based, cross-sectional study in Italian postmenopausal females not affected by diabetes, we showed a link between serum C-peptide and lumbar bone mineral density, suggesting that C-peptide exerts an insulin-independent effect on bone mass. INTRODUCTION: It is well known that type 1 (T1) diabetes, characterized by insulin and C-peptide deficiency, is associated with a low lumbar bone mineral density and an increased risk for fracture. While a role for insulin in the pathogenesis of osteoporosis has been demonstrated, the association between C-peptide and the bone mineral density has not been investigated. We conducted a study in a cohort of 84 postmenopausal women without diabetes to clarify the association between serum C-peptide and the lumbar bone mineral density. METHODS: Participants underwent a bone mineral density evaluation by DXA and biochemical analysis including the C-peptide assay. RESULTS: rteen percent of the population had osteoporosis and 38% had osteopenia. With ANOVA test, we showed that women with the lowest C-peptide concentration had lower lumbar mineral density in comparison to those in all other C-peptide concentration group (p = 0.02 among groups after adjustment). The univariate and multivariate analysis showed that C-peptide was positively associated with both lumbar T-score and Z-score besides other well-known factors like age (with T-score p < 0.001; beta = -0.38) and BMI (with T-score p = 0.009; beta = 0.34), while insulin was not correlated with the lumbar bone mineral density. The area under the receiver operating characteristic (ROC) curve for C-peptide to predict the absence of lumbar osteoporosis was 0.74 (SE = 0.073; p = 0.013). CONCLUSIONS: These results suggest that C-peptide may exert an insulin- and BMI-independent effect on lumbar bone mineral density and that further large-scale studies are needed in order to clarify its role in bone mineralization especially in subjects without diabetes.

In vitro functional response of human tendon cells to different dosages of low-frequency pulsed electromagnetic field.

PURPOSE: Chronic tendinopathy is a degenerative process causing pain and disability. Current treatments include biophysical therapies, such as pulsed electromagnetic fields (PEMF). The aim of this study was to compare, for the first time, the functional in vitro response of human tendon cells to different dosages of PEMF, varying in field intensity and duration and number of exposures. METHODS: Tendon cells, isolated from human semitendinosus and gracilis tendons (hTCs; n = 6), were exposed to different PEMF treatments (1.5 or 3 mT for 8 or 12 h, single or repeated treatments). Scleraxis (SCX), COL1A1, COL3A1 and vascular endothelial growth factor-A (VEGF-A) expression and cytokine production were assessed. RESULTS: None of the different dosages provoked apoptotic events. Proliferation of hTCs was enhanced by all treatments, whereas only 3 mT-PEMF treatment increased cell viability. However, the single 1.5 mT-PEMF treatment elicited the highest up-regulation of SCX, VEGF-A and COL1A1 expression, and it significantly reduced COL3A1 expression with respect to untreated cells. The treated hTCs showed a significantly higher release of IL-1ß, IL-6, IL-10 and TGF-ß. Interestingly, the repeated 1.5 mT-PEMF significantly further increased IL-10 production. CONCLUSIONS: 1.5 mT-PEMF treatment was able to give the best results in in vitro healthy human tendon cell culture. Although the clinical relevance is not direct, this investigation should be considered an attempt to clarify the effect of different PEMF protocols on tendon cells, in particular focusing on the potential applicability of this cell source for regenerative medicine purpose, both in surgical and in conservative treatment for tendon disorders.

Pineal germinoma in a child with interferon-γ receptor 1 deficiency. case report and literature review.

Interferon-γ receptor 1 (IFN-γR1) deficiency is one of the primary immunodeficiencies conferring Mendelian Susceptibility to Mycobacterial Disease (MSMD). Some cases of neoplasms have been recently reported in patients with MSMD, underlying the already known link between immunodeficiency and carcinogenesis. We report the first case of intracranial tumour, i.e. pineal germinoma, in a 11-year-old patient with complete IFN-γR1 deficiency. The first clinical presentation of the genetic immunodeficiency dates back to when the child was aged 2 y and 10 mo, when he presented a multi-focal osteomyelitis caused by Mycobacterium scrofulaceum. The diagnosis of IFN-γR1 deficiency (523delT/523delT in IFNGR1 gene) was subsequently made. The child responded to antibiotic therapy and remained in stable clinical condition until the age of 11 years, when he started complaining of frontal, chronic headache. MRI revealed a solid pineal region mass lesion measuring 20 × 29 × 36 mm. Histological findings revealed a diagnosis of pineal germinoma. The patient received chemotherapy followed by local whole ventricular irradiation with boost on pineal site, experiencing complete remission, and to date he is tumor-free at four years follow-up. Four other cases of tumors have been reported in patients affected by MSMD in our knowledge: a case of Kaposi sarcoma, a case of B-cell lymphoma, a case of cutaneous squamous cell carcinoma and a case of oesophageal squamous cell carcinoma. In conclusion, in patients with MSMD, not only the surveillance of infectious diseases, but also that of tumors is important.

Reciprocal regulation of calcium-/phosphate-regulating hormones in cyclists during the Giro d'Italia 3-week stage race.

Calcium and phosphate are essential for cell functions, and their serum concentrations result from the balance between intestinal absorption, bony storage, and urinary excretion. Fibroblast growth factor 23 (FGF23), expressed by osteocytes and osteoblasts, acts in the kidney, leading to hypophosphatemia and low 1,25-dihydroxycholecalciferol synthesis, but suppresses parathyroid function. The aim of this study was to explore the effects of a high-energy demanding cycling race on this bone-kidney-parathyroid axis. We studied nine cyclists during the 2011 Giro d'Italia stage race. Pre-analytical and analytical phases followed academic and anti-doping recommendations. Serum parathyroid hormone (PTH), 25(OH)D, total calcium, inorganic phosphorus, and plasma FGF23 were measured on days -1, 12, and 22 and corrected for changes in plasma volume. Dietary calcium and phosphorus, anthropometric parameters (height, weight, and body mass index) and indexes of metabolic effort (net energy expenditure, power output) were recorded. Dietary calcium and phosphorus intakes were kept at the same levels throughout the race. Twenty-five (OH)D, PTH, and calcium concentrations remained stable. FGF23 increased 50% with a positive correlation with the indexes of metabolic effort and, consequently, phosphorous decreased, although only in the first half. The strong metabolic effort acts on the bone-kidney-parathyroid system, and the rise in FGF23 plasma concentration might be aimed at maintaining calcium and phosphorus homeostasis.

Plasma myeloperoxidase in patients with erectile dysfunction of arteriogenic- and non-arteriogenic origin: association with markers of endothelial dysfunction.

Endothelial dysfunction and the disruption of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway have been considered the early mechanisms for the development of erectile dysfunction (ED). Myeloperoxidase (MPO), a heme-containing enzyme mainly released by activated neutrophils and monocytes, may contribute to endothelial dysfunction by promoting oxidation of different substrates and thus may play a role in ED. MPO level and its correlation with different plasma biomarkers of endothelial dysfunction were studied in patient with ED of arteriogenic (A-ED) and non-arteriogenic (NA-ED) to assess potential differences between the two ED subgroups. Diagnosis of ED was based on the International Index of Erectile Function Score. Its etiology was classified with penile echo-color Doppler at baseline and after intracavernous injection of prostaglandin E1. MPO, soluble (s) cGMP, sICAM-1, sVCAM-1 and sP-Selectin were measured by enzyme-linked immunosorbent assay. MPO concentration in A-ED was significantly higher compared to control subjects and NA-ED patients. Plasmatic cGMP level resulted lower both in A-ED and in NA-ED patients, whereas no difference has been observed between the two ED groups. sICAM-1 concentration resulted higher in A-ED compared both to controls and NA-ED. sVCAM-1 level was the same in controls, A-ED and NA-ED patients. sP-Selectin concentration resulted higher both in A-ED and in NA-ED patients than in controls, whereas no difference has been observed between the two ED groups. Correlation analysis indicated a positive correlation between plasmatic MPO, sICAM-1 and sP-Selectin levels. MPO may represent an important link between oxidation, inflammation and cardiovascular diseases and may also represent a potential marker to distinguish between the two subgroups of ED patients. Moreover, in ED subjects circulating cGMP may reflect the local signaling dysfunction. The use cGMP as a potential marker for monitoring the disease needs further investigation.

Good response with zinc acetate monotherapy in an adolescent affected by severe Wilson disease.

We describe a 17-year-old girl with haemolytic anaemia as presentation of Wilson disease. The diagnosis was based on the findings of < 20 mg/dl ceruloplasmin serum level, Kayser-Fleischer ring and Coombs-negative haemolytic anaemia. Genetic testing revealed the presence of the H1069Q heterozygous mutation. The patient was treated with Zinc acetate monotherapy, with good response, maintened after 22 months. This case emphasizes the importance of recognizing atypical clinical presentation of Wilson disease, which must always be considered in patients with Coombs-negative haemolytic anaemia. The good clinical response to treatment with zinc acetate monotherapy in our case might lend to consider the use of zinc monotherapy as initial therapy also in symptomatic patients with Wilson disease under close clinical observation. Clinical trials are needed to provide evidence for use of zinc monotherapy as first-line therapy in symptomatic patients with Wilson disease.

Enhancing cranial nerves and cauda equina: an emerging magnetic resonance imaging pattern in metachromatic leukodystrophy and krabbe disease.

We report on three cases of infantile Krabbe disease and one case of infantile metachromatic leukodystrophy showing magnetic resonance (MR) imaging findings of diffuse and coexistent cranial nerve and cauda equina nerve roots enhancement. Such findings may be simultaneous, or even precede, typical white matter abnormalities and, in the appropriate clinical context, may facilitate an earlier diagnosis. There is a rational for the use of contrast agents and craniospinal MR imaging during the first imaging of children with a history of psychomotor regression and clinical evidence of peripheral nerve involvement to exclude differential diagnoses.

Intracranial aneurysm associated with chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is a syndrome characterised by immune deficiency, often presenting familial dominant inheritance and association with autoimmune endocrinopathies. We report on a patient with CMC who died at 5 years of age of a brain haemorrhage following the rupture of a basilar-artery aneurysm. Candida hyphae in the basilar artery were found at autopsy. A common immunologic abnormality in CMC is the failure of patient's T-lymphocytes to produce cytokines, which are essential for expression of cell-mediated immunity to Candida. Therefore, long-term treatment is mandatory.

[Acute urinary retention in a child with acute disseminated encephalomyelitis]. / Encefalomielite acuta disseminata. Descrizione di un caso clinico pediatrico con ritenzione urinaria acuta.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory demyelinating encephalomyelitis with often monosymptomatic abrupt onset, followed by multifocal neurologic symptomatology depending on lesion-site. Diagnosis is made on the basis of characteristic magnetic resonance imaging (MRI) signal alterations. ADEM is sensitive to steroid therapy, immunoglobulins and plasmapheresis, presents usually a monophasic course and disappears completely after 2 or 3 weeks. Resolution of MRI lesions appears usually within 6 months of presentation. We report on a 14-year-old male, admitted to our Emergency Unit because of fever and acute urinary retention with a normal neurological examination. Urinary tract ultrasonography and mictional cystography were normal; electrophysiology showed a mild involvement of the peripheral nervous system and brain and spine MRI revealed disseminated areas of increased signal on T2-weighted sequences suggestive of ADEM. Steroid therapy brought about clinical recovery in a few days. Resolution of lesions on MRI after 4 months and absence of relapses during four-year clinical follow-up confirmed definitive diagnosis. Our case is interesting because, to our knowledge, this is the first literature report with acute urinary retention as predominant symptom in monosymptomatic forms. Another peculiar feature is the absence of associated neurologic symptomatology despite MRI evidence of important brain and spine alterations.

Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: changing distribution and correlation with clinical features and outcome.

BACKGROUND AND AIMS: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. METHODS: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. RESULTS: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p<0.001) among children born from 1990 onwards compared with older children (46% v 70%) while the rate of genotypes 3 and 4 increased significantly (from 8% to 30%). Children infected with genotype 3 had the highest alanine aminotransferase levels and the highest rate of spontaneous viraemia clearance within the first three years of life (32% v 3% in children with genotype 1; p<0.001). Of 96 children enrolled in interferon trials during the survey, 22% definitely lost HCV RNA, including 57% of those with genotypes 2 and 3. CONCLUSION: HCV genotypes 1 and 2 are still prevalent among infected adolescents and young adults in Italy but rates of infection with genotypes 3 and 4 are rapidly increasing among children. These changes could modify the clinical pattern of hepatitis C in forthcoming years as children infected with genotype 3 have the best chance of spontaneous viraemia clearance early in life, and respond to interferon in a high proportion of cases.

Kawasaki's disease in northern Italy: a multicenter retrospective study of 250 patients.

OBJECTIVE: To evaluate (i) the clinical course and outcome in a cohort of 250 children affected with Kawasaki disease (KD) in northern Italy; (ii) the prevalence of coronary aneurysms and their correlation with treatment; and (iii) the prevalence of incomplete and atypical KD in the series as a whole. RESULTS: The male to female ratio was 1.8 to 1 and the median age at diagnosis 37 months. The majority of cases occurred in children under five years, with the youngest patient aged 51 days. Median duration offever was 8 days; median erythrocyte sedimentation rate (ESR) and C Reactive protein (CRP) values, performed before any treatment, were 77 mm/1st h and 10.4 mg/dl respectively. Median haemoglobin (Hb) levels was 9.2 g/dl and median platelet (PTL) count 408,000/mm3. Out of 250 patients, 209 (83.6%) fulfilled all criteria for the diagnosis of KD whilst 41/250 (16.4%) had an incomplete disease and 11/250 (4.4%) had an atypical onset. Fifty-four children (21.6%) were treated with aspirin alone (50-80 mg/kg/day, during the acute phase), while 196/250 (78.4%) were given aspirin (50-80 mg/kg day, during the acute phase and then 3-5 mg/Kg/day) and high-dose intravenous gammaglobulin (IVIG, 400 mg/Kg/day or 2 g/Kg/day). Coronary artery abnormalities, including aneurysms and dilatation, were reported in 7/54 patients (5 males and 2 females) who had not received IVIG and 53/196 patients (27 males and 26 females) who were treated with the IVIG in addition to aspirin. Other clinical manifestations included abdominal pain/diarrhoea (11), arthritis (10), hydrops of the gallbladder (8), disseminated intravascular coagulation (3), and hemiparesis (1). All patients except one infant are still alive. In most of the patients coronary alterations normalised, while in 20 patients they persisted for more than one year; in 12/20 patients they were permanent. CONCLUSION: Pediatricians should be aware of the increasing number of children with atypical and incomplete KD, in order to diagnose and treat the disease even in the absence of all typical manifestations and to prevent coronary complications.

An epidemiological survey of hepatitis C virus infection in Italian children in the decade 1990-1999.

BACKGROUND: A retrospective-prospective survey of Italian children with hepatitis C virus (HCV) infection was planned in 1998 to explore the epidemiologic features of infection during the past decade. METHODS: Anti-HCV-positive patients (or HCV RNA-positive infants) aged 1 month to 16 years, consecutively observed in 20 pediatric Institutions, were considered. An anonymous epidemiologic questionnaire based on clinical records was used. RESULTS: From 1990 through March 1999, 606 patients were observed (296 boys, average age 5.8 years). Maternal infection (46% of cases) and blood transfusions (34%) were the most frequent risk factors. Of 279 infected mothers, 61% did not recall a putative source of infection (by history, many could possibly have had exposure through routes such as therapeutic injections with nondisposable material), whereas 94 (34%) admitted drug abuse, including 49 (17%) coinfected with human immunodeficiency virus (HIV). Only 157 (26%) children were born after 1991: 90% of their mothers were infected (11% were HIV coinfected vs. 25% mothers of older children, P < 0.01). CONCLUSIONS: Maternal infection is a prominent source of pediatric HCV infection in Italy. The fact that most mothers had a history of covert exposure to HCV, probably through percutaneous routes that are no longer operating, and that the number of those with HIV coinfection has decreased suggests that the frequency of pediatric infection could decrease in the future.

Jagged-1 mutation analysis in Italian Alagille syndrome patients.

Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice-site, and two missense mutations. The two novel missense mutations were clustered in the 5' region, while the remaining mutations were scattered throughout the gene. The spectrum of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dupl8bp, which was shown to lead to an abnormal JAG1 mRNA, resulting in a premature stop codon. With the exception of the missense mutations, the majority of the JAG1 mutations are therefore likely to produce truncated proteins. Since the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations, our study further supports the hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis. Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype.

Clinical and biological characteristics of immunopathological disease-related erythema nodosum in children.

We report a series of 22 children with idiopathic, drug unrelated erythema nodosum (EN) admitted to our Department. In 5 of them an history of streptococcal pharyngitis was referred; the remaining patients came to us with a diagnosis of "EN of unknown origin". Acute phase reactants, immunoglobulins, stool alpha1 antitrypsin, ANA, anti dsDNA antibodies and ANCA assay, chest roentgenogram, tuberculin test, and ophthalmologic assessment were performed in all patients. Etiologic diagnosis was made in 16 patients: Streptococcal pharyngitis (5 cases), chronic inflammatory bowel disease, IBD (3 cases), Behçet syndrome (2 cases), Yersinia enteritis (2 cases), infectious mononucleosis, atypical mycobacterial infection, immunodeficiency related infection, and SLE-like syndrome due to C4 deficiency (1 case each). We found oral/scrotal aphthae in 3 cases, gastrointestinal symptoms in 5 cases, arthritis in 3 cases. Acute phase reactants were positive in 16 patients without correlation to the underlying disease. Conversely, the increased alpha1 antitrypsin stool excretion and IgA serum concentration seemed to represent helpful indicators of IBD and Behçet syndrome, respectively. Proinflammatory cytokine pattern showed increased IL6 serum concentrations both in infectious and in non infectious disease-related EN, whereas a minor involvement of TNF was found in these patients.

Syndromic variability of Wilson's disease in children. Clinical study of 44 cases.

BACKGROUND: In children with Wilson's disease, no clinical or laboratory data are specific for diagnosis as in adult age. AIM: Clinical aspects and parameters of copper metabolism in a large series of pediatric cases are evaluated to establish certain criteria for diagnosis and for correct treatment, even in difficult cases. METHODS: In 44 children with Wilson's disease, clinical aspects, histological features, laboratory parameters and data of copper metabolism have been studied. Forty patients, treated with penicillamine, were followed up (median 77 months). RESULTS: The 44 cases were classified as: asymptomatic forms (nine cases, six of them siblings of affected subjects), chronic hepatitis (23 cases), hepatocerebral manifestations (four cases), decompensated cirrhosis (six cases), fulminant hepatic failure with hemolytic anemia (two cases). Ceruloplasmin levels were abnormal in 37 out of 43 tested cases, but normal in six (14%) who showed high basal and after penicillamine load urine copper excretion and increased hepatic copper content. Urine copper concentration was pathological in 35 out of 42 tested cases (83%), but normal in seven patients under six years. Hepatic copper levels were very high in all the 20 tested patients. Under treatment, 27 children had favourable outcome. One patient showed no evolution of disease, seven patients worsened because of non-compliance to the therapy (one underwent successful liver transplantation) or severe side effects. Five patients with failure died. CONCLUSIONS: Wilson's disease in children may present with a broad clinical spectrum, but the liver involvement is by far the most prevalent. The early diagnosis, based on clinical suspicion and results of copper metabolism investigation (including hepatic copper content evaluation in difficult cases) and appropriate treatment can prevent the progression of the disease.