Tissue-inhibitors of metalloproteinase-1 and vascular-endothelial growth-factor in severe haemophilia A children on low dose prophylactic recombinant factor VIII: Relation to subclinical arthropathy.

BACKGROUND: Subclinical synovitis occur long before clinical haemophilic arthropathy (HA). New biomarkers are needed for early detection of HA. AIM: To compare the levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF)in severe haemophilia A boys on prophylaxis and on-demand therapy to healthy boys and correlate them with the haemophilia joint health score (HJHS) & the Denver magnetic resonance imaging (MRI) scale; hence, determine their values in early detection of HA. METHODS: Haemophilia joint health score, serum TIMP-1, VEGF and Denver MRI score were assessed in 50 boys with severe haemophilia A (31 on prophylactic factor VIII therapy (62%) with a dose of 15 IU/kg/twice weekly) and 50 age-matched healthy boys. RESULTS: Boys with severe haemophilia A had significantly higher TIMP-1 240 ng/mL, SD200-350 (P < .001) and VEGF 600 pg/mL, SD400-1100 (P < .001). Their mean HJHS was 4.5 ± 3.0 (0-11) and their mean Denver MRI score was 5.55 ± 1.6 (2.00-8.00). A significant positive correlation was found between TIMP-1 and VEGF (P < .001), BMI Z-score (P = .029), HJHS (P = .041)and total MRI score (<.001). Significant correlations were found between VEGF and age (P < .001), HJHS (P = .003) and total MRI score (P < .001). Boys with severe haemophilia A on prophylaxis therapy had significantly lower HJHS (P = .021), VEGF (P < .001), TIMP-1 (P = .002) and total MRI score (P = .021) than those on on-demand therapy. Receiver operating characteristic curve, defined a cut-off value of 160 ng/mL for TIMP-1 with a sensitivity of 90% and specificity of 60% and that of 350 pg/mL for VEGF with a sensitivity of 78% and specificity of 88% for discrimination between severe haemophilia A and healthy boys. CONCLUSION: Vascular endothelial growth factor and TIMP-1 can be used for early detection of HA. Further prospective studies should include larger study populations. In addition, studies should address the role of various anti-VEGFs as potential therapy for HA and their impact on prevention and treatment of HA.

Effect of low-dose factor VIII prophylaxis therapy on bone mineral density and 25(OH) vitamin D level in children with severe haemophilia A.

BACKGROUND: Decreased bone mineral density (BMD) is a significant morbidity in haemophilia. Vitamin D is important for the bone health of people with haemophilia. Regular factor VIII prophylaxis can prevent bleeding and arthropathy. AIM: To determine the 25(OH) vitamin D level in severe haemophilia A patients and correlate it to their Hemophilia Joint Health Score (HJHS) and dual-energy X-ray absorptiometry (DEXA). We also compared the 25(OH) vitamin D and DEXA in haemophilia A and healthy children and in haemophilia A children on prophylaxis versus on-demand therapy. METHODS: Fifty severe haemophilia A patients were compared to 50 age-matched healthy boys. Patients were recruited from the Pediatric Hematology Clinic, Ain Shams University from May 2017 to April 2018. Full medical history was taken with emphasis on frequency of bleeding episodes, duration and amplitude of pain assessed by the pain score. Weight, height, body mass index and HJHS were assessed. 25(OH) vit-D3, calcium, phosphorus and alkaline phosphatase were measured. BMD was assessed using Lunar DEXA, paediatric software. RESULTS: People with haemophilia had significantly lower 25(OH) vit-D3 (P < .001) and DEXA z-score (P < .001) than controls. Seventy per cent of patients were on factor VIII prophylaxis twice weekly (15U/kg/dose). Significant difference was found regarding DEXA z-score (P = .012), 25(OH) vit-D3 (P = .033) and HJHS (P = .022) among patients on prophylaxis and on-demand therapy. CONCLUSION: Severe haemophilia A patients showed significantly lower 25(OH) vit-D3 and DEXA than controls. Hence, vitamin D deficiency should be tested in all people with haemophilia for early diagnosis and treatment. Low-dose prophylaxis in severe haemophilia preserves BMD and increases vitamin D. Further studies are required to evaluate the effect of different prophylaxis protocols on BMD and haemophilic arthropathy.

Pulmonary manifestations in young Gaucher disease patients: Phenotype-genotype correlation and radiological findings.

BACKGROUND: Although pulmonary involvement is important orbidity in Gaucher disease (GD), it is previously reported to be rare. Moreover, no epidemiological studies described its prevalence specifically in children. The clinical spectrum and risk determinants for this complication and its long-term response to therapy are unknown. AIM: To assess the prevalence of clinical and radiological pulmonary involvement in pediatric GD patients and its relation to Gaucher severity and genotype. METHODS: Forty-eight GD patients were studied focusing on pulmonary and neurological manifestations with assessment of severity scoring index (SSI; a Gaucher specific scale). Detailed enzyme replacement therapy (ERT) history was taken regarding dose, duration, and effect on pulmonary manifestations. Genotype was performed to 30 patients. Radiological investigations included plain chest-radiography (CXR), high-resolution CT (HRCT), and hepatic and splenic volumes. RESULTS: Fifteen patients had type 1 (31.2%) and 33 patients had type 3 GD (68.8%). The most common mutation was L483P detected in 25 patients (83.3%). Sixteen patients had recurrent chest wheeze (33%). CXR showed pulmonary findings in 17 patients (35.4%) while HRCT-chest showed affection in 31 patients (64.6%). The ground-glass pattern was present in 14 patients (29.1%), reticulonodular infiltration in 9 patients (18.8%), air trapping in 6 patients (12.5%), and bronchiectatic changes in two patients (4.2%). Univariate logistic regression analysis for predictors of abnormal HRCT-chest was negatively correlated with platelets (P = .01) and hemoglobin (P = .018) and positively correlated with recurrent chest wheezing (P = .019), abnormal CXR (P = .007), and SSI (P = .009). CONCLUSION: Pulmonary involvement is a prevalent morbidity of GD with variable presentations. CXR for early detection of pulmonary involvement in GD is safe and highly predictive.

Soluble urokinase plasminogen activator receptor in type 1 diabetic children, relation to vascular complications.

BACKGROUND: Endothelial dysfunction caused by chronic inflammation is the cornerstone of vascular complications in type 1 Diabetes-Mellitus (T1DM). Soluble Urokinase Plasminogen Activator Receptor (SuPAR) is a novel marker of inflammation and endothelial dysfunction. AIM: To evaluate SuPAR in T1DM children and correlate it to diabetic vascular complications. METHODS: Seventy T1DM children and 40 matched healthy controls were studied focusing on disease duration, insulin therapy and symptoms of diabetic complications. Blood-pressure, fundus and screening for peripheral-neuropathy were done. Fasting lipid profile, fraction-C of glycosylated hemoglobin (HbA1c%), Urinary albumin excretion (UAE), estimated-glomerular filtration rate (eGFR) and SuPAR were measured. Internal aortic diameter was measured with calculation of aortic distensibility and stiffness index. RESULTS: Sixteen T1DM patients(22.9%) had peripheral neuropathy, 12(17%) had nephropathy and none had retinopathy. SuPAR was significantly elevated in diabetic nephropathy (p < 0.01) and neuropathy (p < 0.01). Aortic stiffness index was significantly higher (p < 0.01) whereas, aortic strain and distensibility were significantly lower (p < 0.01) in T1DM than controls. SuPAR was significantly correlated to disease duration (p < 0.01), systolic blood pressure (p < 0.01), total cholesterol (p < 0.01), triglycerides (p < 0.01), UAER (p < 0.01) and aortic strain (0.013). CONCLUSION: Increased SuPAR early in diabetes might become a useful indicator of developing vascular complications. Further prospective studies are needed to determine the cut-off level of SuPAR for detection of T1DM and its complications.

Psychiatric manifestations in Egyptian Gaucher patients on enzyme replacement therapy.

OBJECTIVES: Gaucher disease (GD) may include psychiatric symptoms as a part of its wide spectrum of manifestations, with several reports describing its association with mood or psychotic symptoms. We investigated the presence of psychiatric manifestations in an Egyptian sample of Gaucher Disease (GD) patients. METHODS: Our sample consisted of 22 GD patients (diagnosed by low glucocerebrosidase (GBA) activity in leukocytes or fibroblasts and molecular analysis by full (GBA) gene sequencing). 13 patients were classified as GD type 1 and 9 patients as GD type 3. We assessed the presence of psychiatric symptoms using the Mini-international neuropsychiatric interview (M.I.N·I) and the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) tools. Arabic versions were used. RESULTS: The results showed that 41% of the sample had psychiatric disorders, with the most common being depression. None was receiving any form of psychiatric treatment. We found no statistically significant association between the presence of psychiatric disorders and any of the clinical variables of GD, its phenotype, or genotype. CONCLUSION: The current results suggest that GD patients are susceptible to psychiatric disorders. However, these results need to be replicated on a wider scale. These findings are of ultimate importance, considering the lack of integrated services addressing both the medical and psychological aspects of inborn errors of metabolism in many countries.