Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children

Highly active antiretroviral therapy (HAART) may be a contributory factor for a decreased bone mass and altered bone metabolism in HIV-infected children. However, the evolution of bone mineral density (BMD) and bone metabolism during HAART has not been studied yet. In the current longitudinal study we monitored the changes of BMD and bone metabolism over a period of 12 months. Thirty-two HIV-infected children (15 girls and 17 boys), aged from 6.3 to 17.7 yr, with a long duration of HAART exposure (40.0 months at baseline) were enrolled in the study. As a control group, 381 healthy volunteers of comparable age were assessed. BMD was measured at the lumbar spine and whole skeleton by dual-energy x-ray absorptiometry. Bone-specific alkaline phosphatase (BALP, as bone formation index) and N-terminal telopeptide of type I collagen (as bone resorption index) were measured in serum and urine, respectively. BMD values at baseline were significantly lower at all skeletal sites than those of control subjects. The annual increment of spine BMD was comparable to normal, whereas that of the whole skeleton was significantly lower (P < 0.04). BALP and N-terminal telopeptide of type I collagen concentrations were significantly higher compared with controls at baseline and at follow-up. BALP annual changes of HIV patients were significantly different from normal. Our data confirm the presence of low BMD and bone metabolism derangement in HIV-infected children treated with HAART. The role of possible therapeutic approach to restore bone mass and metabolism should be assessed in pediatrics

Congenital hypothyroidism with eutopic thyroid gland : analysis of clinical and biochemical features at diagnosis and after re-evaluation

Context: In recent years changes in screening strategies for congenital hypothyroidism (CH) led to an increased detection of mild forms of CH, associated with eutopic thyroid gland. Objectives: We aimed to determine the clinical evolution of CH with eutopic thyroid gland and to find out prognostic factors at diagnosis and follow-up. Patients and Methods: We retrospectively analyzed agroup of84 children withCH andeutopic thyroid gland treated at our institution. They all underwent clinical re-evaluation after the age of 3, based on thyroid function testing after L-thyroxine therapy withdrawal, thyroid ultrasonography, and 123I scintigraphy with perchlorate discharge test. Genetic analysis was performed in selected cases. Results: At re-evaluation, 34.5% of patients showed permanent hypothyroidism and needed L-thyroxine reintroduction, 27.4% had persistent hyperthyrotropinemia (TSH5-10mU/L), and 38.1% had transient hypothyroidism. Major risk factors for permanent CH were prematurity, first-degree familial history of goiter/nodules, thyroid hypoplasia at diagnosis, and high L-thyroxine requirements at follow-up. Iodine organification defects were found in 29.7% of patients, 30% of whom harbored DUOX2 mutations. TSH receptor gene mutations were found in 8.7% of patients with persistent thyroid dysfunction and negative perchlorate discharge test. Conclusions: Only one-third of patients with CH and eutopic thyroid gland needed to continue L-thyroxine therapy after re-evaluation. A frequent finding was the persistence of mild hyperthy-rotropinemia. The evolution of CH remains difficult to predict, although different clinical features might suggest different outcomes. Mutations in the genes commonly linked to mild forms of CH were documented in a minority of cases. Copyrigh

Congenital hypothyroidism

Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism

Genetic defects of hydrogen peroxide generation in the thyroid gland

Hydrogen peroxide (H2O2) is a key element in thyroid hormone biosynthesis. It is the substrate used by thyroid peroxidase for oxidation and incorporation of iodine into thyroglobulin, a process known as organification. The main enzymes composing the H2O2-generating system are the dual oxidase 2 (DUOX2) and the recently described DUOX maturation factor 2 (DUOXA2). Defects in these reactions lead to reduced thyroid hormone synthesis and hypothyroidism, with consequent increased TSH secretion and goiter. Since the first report in 2002 of DUOX2 mutations causing congenital hypothryoidism (CH), to date 25 different mutations have been described. Affected patients show a positive perchlorate discharge test and high phenotypic variability, ranging from transient to permanent forms of CH. Up to now, only two cases of CH due to DUOXA2 defects have been published. They also suggest the existence of a great genotype-phenotype variability. The phenotypic expression is probably influenced by genetic background and environmental factors. DUOX and DUOXA constitute a redundant system in which DUOX1/DUOXA1 can at least partially replace the function of DUOX2/DUOXA2. Furthermore, increased nutritional iodide could ensure a better use of H2O2 provided by DUOX1

Pediatric HIV infection and bone health : an emerging challenge

The available data indicate that HIV-infected children and adolescents have reduced bone mass compared to healthy peers. The increased survival due to the control of HIV infection by potent antiretroviral treatment, exposes patients to the achievement of a reduced peak bone mass and to an increased fracture risk during adult life. Reduced bone mass in HIV-infected children is the result of altered bone metabolism, showing significantly increased bone resorption rate. Both infection per se and the use of certain antiretroviral compounds seem to contribute to the altered metabolism. Preventative measures to improve bone health are thus necessary in all young patients that exhibit low bone mass measurements and altered bone metabolism

Analysis of bone mineral content in horizontally HIV-infected children naive to antiretroviral treatment

Low bone mass is a frequent finding in HIV-infected individuals. Reduced bone mass has been found in vertically infected children who are receiving antiretroviral treatment. Little is known about bone mass in horizontally infected young patients who are naive to antiretroviral therapy. We measured the bone mineral content (BMC) at the lumbar spine and in the whole skeleton by using dual-energy X-ray absorptiometry (DXA) in 16 HIV-infected children (age 9.3 +/- 3.9 years) naive to antiretroviral treatment, and in 119 healthy children (age 9.7 +/- 3.3 years). Thirteen patients were also pair-matched by anthropometric measures, sex, and age with healthy children. Median spine BMC of HIV-infected children was 14.9 g (8.2-39.2 g), and whole body BMC was 1106.1 g (55.5-2344.1 g). Spine BMC of healthy children was 18.6 g (6.8-52.2 g), and whole body BMC was 1213.5 g (541.0-2722.0 g). Multivariate analysis showed a mean difference of spine BMC values of 0.004 g (P = 0.64) between the two groups. Similarly, the whole body BMC difference between the two groups (0.001 g) was not statistically significant (P = 0.55). Mean spine BMC measurements in the case-control evaluation were 21.1 g (9.7 g) (patients), and 22.3 g (6.9 g) (controls). Whole body BMC measurements of patients and controls were 1258.5 g (539.6 g) and 1311.1 g (479.2 g), respectively. In both cases the differences were not significant. The duration of HIV infection did not relate to BMC values. In conclusion, horizontally HIV-infected children naive to antiretroviral therapy have bone mineral measurements comparable to those of healthy children

Alterations in circulating osteoimmune factors may be responsible for high bone resorption rate in HIV-infected children and adolescents

Objectives: Bone metabolism derangements have been reported in HIV-infected children and adolescents. Nuclear factor kappa B ligand (RANKL) and osteoprotegerin potently stimulate and inhibit, respectively, osteoclast formation and activity. We investigated the possible role of RANKL and osteoprotegerin on bone metabolism alterations in paediatric patients. Design: A prospective controlled longitudinal study. Measurements were obtained before and 6 months after switching antiretroviral regimen. Methods: We studied 27 vertically HIV-infected children and adolescents (aged 4.9-17.3 years) on long-term HAART (70.1 +/- 1.5 months). All patients received lamivudine, stavudine and one protease inhibitor (PI). During follow-up, the PI was replaced with efavirenz and stavudine with tenofovir. We also enrolled 336 healthy children, aged 4.8-17.9 years. Concentrations of bone-specific alkaline phosphatase (BALP), N-terminal telopeptide of type I collagen (NTx), RANKL, and osteoprotegerin were measured at baseline and 6 months after switching. Results: BALP serum concentrations and NTx urine levels of HIV-infected patients were significantly higher than those of healthy children both at baseline and after 6 months (P < 0.001). Baseline osteoprotegerin and RANKL concentrations of HIV-infected patients were significantly higher than in healthy children (P < 0.0001). Both concentrations decreased after 6 months, and RANKL levels were no longer different to controls. At baseline the RANKL/osteoprotegerin ratio was significantly higher (P = 0.02) in HIV-infected children (0.27 +/- 0.07) compared with healthy children (0.078 +/- 0.01). Conclusion: A marked alteration in the RANKL/osteoprotegerin system is present in patients receiving PI-based HAART. Short-term data indicate that replacing stavudine and PI with tenofovir and efavirenz restores the RANKL/osteoprotegerin equilibrium, and may thus lead to a reduction in the bone resorption rate

Differential effect of age, gender and pubert&#224; on bone formation rate assessed by measurements of bone-specific alcaline phosphatase in healthy Italian children and adolescents

Bones undergo intensive modeling during growth, a process involving both formation and resorption processes. Bone formation can be accurately monitored by measurements of bone-specific alkaline phosphatase (BAP) in serum. The lack of appropriate reference values has hampered the use of BAP in pediatric subjects. The purposes of the present study were to verify the effect of age, gender, and puberty on BAP concentration in healthy children, and to generate reference curves. Morning blood samples were collected from 239 healthy children and adolescents (113 boys), aged 4.5-20.9 years. Anthropometric measurements and pubertal stage were recorded. Blood samples were also obtained from 37 healthy young adults (13 men), aged 21.5-30.2 years. BAP concentration varied significantly with age, showing a peak at age 10-12 years in girls and 12-14 years in boys. Prepubertal concentration of BAP was six- to sevenfold higher than in healthy adults. We observed significantly higher BAP values at the beginning of puberty (stage II) compared to prepubertal stage in both sexes. The effect of puberty was independent from age and gender. We demonstrated that BAP serum concentration varies with age in children and adolescents, and we provided equations to calculate reference values. Because BAP concentrations vary markedly according to the pubertal stage, the values of BAP obtained in single patients should be compared to reference considering not only age and sex, but also the stage of pubertal development